|
Binding affinity towards human gonadotropin-releasing hormone receptor
|
None
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidine-2,4-dione derivatives as potent GnRH receptor antagonists.
Year : 2003
Volume : 13
Issue : 20
First Page : 3617
Last Page : 3622
Authors : Guo Z, Chen Y, Wu D, Zhu YF, Struthers RS, Saunders J, Xie Q, Chen C.
Abstract : The synthesis and SAR studies of thieno[2,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists to treat reproductive diseases are discussed. It was found that the 2-(2-pyridyl)ethyl group on the 5-aminomethyl functionality of the core structure was a key feature for good receptor binding activity. SAR study of the 6-(4-aminophenyl) group suggests that hydrophobic substituents were preferred. The best compound from this series had binding affinity (K(i)) of 0.4 nM to the human GnRH receptor.
|
Tested for antagonist concentration required to inhibit specific binding of [125I]leuprorelin to LHRH receptor in monkey (chinese hamster ovary (CHO) cells)
|
Cercopithecidae
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor.
Year : 2003
Volume : 46
Issue : 1
First Page : 113
Last Page : 124
Authors : Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M.
Abstract : We have previously disclosed the first potent and orally effective non-peptide antagonist for the human luteinizing hormone-releasing hormone (LHRH) receptor, a thieno[2,3-b]pyridin-4-one derivative, T-98475 (1). Extensive research on developing non-peptide LHRH antagonists has been carried out by employing a strategy of replacing the thienopyridin-4-one nucleus with other heterocyclic surrogates. We describe herein the design and synthesis of a series of thieno[2,3-d]pyrimidine-2,4-dione derivatives containing a biaryl moiety, which led to the discovery of a highly potent and orally active non-peptide LHRH antagonist, 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9k: TAK-013). Compound 9k showed high binding affinity and potent in vitro antagonistic activity for the human receptor with half-maximal inhibition concentration (IC(50)) values of 0.1 and 0.06 nM, respectively. Oral administration of 9k caused almost complete suppression of the plasma LH levels in castrated male cynomolgus monkeys at a 30 mg/kg dose with sufficient duration of action (more than 24 h). The results demonstrated that the thienopyrimidine-2,4-dione core is an excellent surrogate for the thienopyridin-4-one and that thienopyrimidine-2,4-diones and thienopyridin-4-ones constitute a new class of potent and orally bioavailable LHRH receptor antagonists. Furthermore, molecular modeling studies indicate that the unique methoxyurea side chain of 9k preferentially forms an intramolecular hydrogen bond between the aniline NH and the methoxy oxygen atom. The hydrogen bond will shield the hydrogen bonding moieties from the solvent and reduce the desolvation energy cost. It is therefore speculated that the intramolecular hydrogen bond resulting from judicious incorporation of an oxygen atom into the terminal alkyl group of the urea may increase the apparent lipophilicity to allow increased membrane permeability and consequently to improve the oral absorption of 9k in monkeys. On the basis of its profile, compound 9k has been selected as a candidate for clinical trials and it is expected that it will provide a new class of potential therapeutic agents for the clinical treatment of a variety of sex-hormone-dependent diseases.
|
Tested for inhibition of arachidonic acid(AA) release from CHO cells in Monkey
|
Cercopithecidae
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor.
Year : 2003
Volume : 46
Issue : 1
First Page : 113
Last Page : 124
Authors : Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M.
Abstract : We have previously disclosed the first potent and orally effective non-peptide antagonist for the human luteinizing hormone-releasing hormone (LHRH) receptor, a thieno[2,3-b]pyridin-4-one derivative, T-98475 (1). Extensive research on developing non-peptide LHRH antagonists has been carried out by employing a strategy of replacing the thienopyridin-4-one nucleus with other heterocyclic surrogates. We describe herein the design and synthesis of a series of thieno[2,3-d]pyrimidine-2,4-dione derivatives containing a biaryl moiety, which led to the discovery of a highly potent and orally active non-peptide LHRH antagonist, 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9k: TAK-013). Compound 9k showed high binding affinity and potent in vitro antagonistic activity for the human receptor with half-maximal inhibition concentration (IC(50)) values of 0.1 and 0.06 nM, respectively. Oral administration of 9k caused almost complete suppression of the plasma LH levels in castrated male cynomolgus monkeys at a 30 mg/kg dose with sufficient duration of action (more than 24 h). The results demonstrated that the thienopyrimidine-2,4-dione core is an excellent surrogate for the thienopyridin-4-one and that thienopyrimidine-2,4-diones and thienopyridin-4-ones constitute a new class of potent and orally bioavailable LHRH receptor antagonists. Furthermore, molecular modeling studies indicate that the unique methoxyurea side chain of 9k preferentially forms an intramolecular hydrogen bond between the aniline NH and the methoxy oxygen atom. The hydrogen bond will shield the hydrogen bonding moieties from the solvent and reduce the desolvation energy cost. It is therefore speculated that the intramolecular hydrogen bond resulting from judicious incorporation of an oxygen atom into the terminal alkyl group of the urea may increase the apparent lipophilicity to allow increased membrane permeability and consequently to improve the oral absorption of 9k in monkeys. On the basis of its profile, compound 9k has been selected as a candidate for clinical trials and it is expected that it will provide a new class of potential therapeutic agents for the clinical treatment of a variety of sex-hormone-dependent diseases.
|
Antagonist concentration required to inhibit specific binding of [125I]leuprorelin to human luteinizing releasing hormone receptor in cloned chinese hamster ovary (CHO) cells.
|
None
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor.
Year : 2003
Volume : 46
Issue : 1
First Page : 113
Last Page : 124
Authors : Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M.
Abstract : We have previously disclosed the first potent and orally effective non-peptide antagonist for the human luteinizing hormone-releasing hormone (LHRH) receptor, a thieno[2,3-b]pyridin-4-one derivative, T-98475 (1). Extensive research on developing non-peptide LHRH antagonists has been carried out by employing a strategy of replacing the thienopyridin-4-one nucleus with other heterocyclic surrogates. We describe herein the design and synthesis of a series of thieno[2,3-d]pyrimidine-2,4-dione derivatives containing a biaryl moiety, which led to the discovery of a highly potent and orally active non-peptide LHRH antagonist, 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9k: TAK-013). Compound 9k showed high binding affinity and potent in vitro antagonistic activity for the human receptor with half-maximal inhibition concentration (IC(50)) values of 0.1 and 0.06 nM, respectively. Oral administration of 9k caused almost complete suppression of the plasma LH levels in castrated male cynomolgus monkeys at a 30 mg/kg dose with sufficient duration of action (more than 24 h). The results demonstrated that the thienopyrimidine-2,4-dione core is an excellent surrogate for the thienopyridin-4-one and that thienopyrimidine-2,4-diones and thienopyridin-4-ones constitute a new class of potent and orally bioavailable LHRH receptor antagonists. Furthermore, molecular modeling studies indicate that the unique methoxyurea side chain of 9k preferentially forms an intramolecular hydrogen bond between the aniline NH and the methoxy oxygen atom. The hydrogen bond will shield the hydrogen bonding moieties from the solvent and reduce the desolvation energy cost. It is therefore speculated that the intramolecular hydrogen bond resulting from judicious incorporation of an oxygen atom into the terminal alkyl group of the urea may increase the apparent lipophilicity to allow increased membrane permeability and consequently to improve the oral absorption of 9k in monkeys. On the basis of its profile, compound 9k has been selected as a candidate for clinical trials and it is expected that it will provide a new class of potential therapeutic agents for the clinical treatment of a variety of sex-hormone-dependent diseases.
|
Tested for inhibition of arachidonic acid(AA) release from CHO cells in Human
|
None
|
0.06
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor.
Year : 2003
Volume : 46
Issue : 1
First Page : 113
Last Page : 124
Authors : Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M.
Abstract : We have previously disclosed the first potent and orally effective non-peptide antagonist for the human luteinizing hormone-releasing hormone (LHRH) receptor, a thieno[2,3-b]pyridin-4-one derivative, T-98475 (1). Extensive research on developing non-peptide LHRH antagonists has been carried out by employing a strategy of replacing the thienopyridin-4-one nucleus with other heterocyclic surrogates. We describe herein the design and synthesis of a series of thieno[2,3-d]pyrimidine-2,4-dione derivatives containing a biaryl moiety, which led to the discovery of a highly potent and orally active non-peptide LHRH antagonist, 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9k: TAK-013). Compound 9k showed high binding affinity and potent in vitro antagonistic activity for the human receptor with half-maximal inhibition concentration (IC(50)) values of 0.1 and 0.06 nM, respectively. Oral administration of 9k caused almost complete suppression of the plasma LH levels in castrated male cynomolgus monkeys at a 30 mg/kg dose with sufficient duration of action (more than 24 h). The results demonstrated that the thienopyrimidine-2,4-dione core is an excellent surrogate for the thienopyridin-4-one and that thienopyrimidine-2,4-diones and thienopyridin-4-ones constitute a new class of potent and orally bioavailable LHRH receptor antagonists. Furthermore, molecular modeling studies indicate that the unique methoxyurea side chain of 9k preferentially forms an intramolecular hydrogen bond between the aniline NH and the methoxy oxygen atom. The hydrogen bond will shield the hydrogen bonding moieties from the solvent and reduce the desolvation energy cost. It is therefore speculated that the intramolecular hydrogen bond resulting from judicious incorporation of an oxygen atom into the terminal alkyl group of the urea may increase the apparent lipophilicity to allow increased membrane permeability and consequently to improve the oral absorption of 9k in monkeys. On the basis of its profile, compound 9k has been selected as a candidate for clinical trials and it is expected that it will provide a new class of potential therapeutic agents for the clinical treatment of a variety of sex-hormone-dependent diseases.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR F272L
|
Homo sapiens
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR M24A
|
Homo sapiens
|
240.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR M24I
|
Homo sapiens
|
108.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR M24T
|
Homo sapiens
|
193.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR N27A
|
Homo sapiens
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR N27E
|
Homo sapiens
|
8.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR A50T
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR T51A
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR E111A
|
Homo sapiens
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR E111K
|
Homo sapiens
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR E111Q
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR L112A
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR L112F
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR L112K
|
Homo sapiens
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR K115Q
|
Homo sapiens
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR L117A
|
Homo sapiens
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR S118A
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR K121A
|
Homo sapiens
|
470.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR S124A
|
Homo sapiens
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR S168A
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR S168I
|
Homo sapiens
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR H182A
|
Homo sapiens
|
0.3
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR H182E
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR S186D
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR S186K
|
Homo sapiens
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Q189A
|
Homo sapiens
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Q189E
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Q189K
|
Homo sapiens
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Q189P
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR T190K
|
Homo sapiens
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR K191E
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR S203E
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR S203K
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR S203P
|
Homo sapiens
|
1.4
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR S203Q
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Q208D
|
Homo sapiens
|
9.7
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Q208E
|
Homo sapiens
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR W280F
|
Homo sapiens
|
2.3
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Y283F
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Y284F
|
Homo sapiens
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Y284L
|
Homo sapiens
|
12.1
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Y290F
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Y290L
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR Y290Q
|
Homo sapiens
|
1.1
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR W291F
|
Homo sapiens
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR D293A
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR D293K
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR D293N
|
Homo sapiens
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR D293E
|
Homo sapiens
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR E295A
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR E295K
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR E295Q
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR L300A
|
Homo sapiens
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR L300K
|
Homo sapiens
|
5.2
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR L300V
|
Homo sapiens
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR D302A
|
Homo sapiens
|
192.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR D302N
|
Homo sapiens
|
115.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR D302Q
|
Homo sapiens
|
148.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR N305A
|
Homo sapiens
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR N305D
|
Homo sapiens
|
4.3
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR N305K
|
Homo sapiens
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR H306A
|
Homo sapiens
|
23.4
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR H306E
|
Homo sapiens
|
94.9
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR H306K
|
Homo sapiens
|
242.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR F309L
|
Homo sapiens
|
6.3
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR F309Q
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR F313L
|
Homo sapiens
|
24.4
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR N315A
|
Homo sapiens
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from mutant GnRHR, GnRHR N315D
|
Homo sapiens
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from human wild type GnRHR
|
Homo sapiens
|
2.5
nM
|
|
Journal : J. Med. Chem.
Title : Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
Year : 2006
Volume : 49
Issue : 2
First Page : 637
Last Page : 647
Authors : Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
Abstract : Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR M24I mutant expressed in COS7 cells
|
Homo sapiens
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR N27A mutant expressed in COS7 cells
|
Homo sapiens
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR Q208E mutant expressed in COS7 cells
|
Homo sapiens
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR Y284L mutant expressed in COS7 cells
|
Homo sapiens
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR L300A mutant expressed in COS7 cells
|
Homo sapiens
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR D302A mutant expressed in COS7 cells
|
Homo sapiens
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR D302N mutant expressed in COS7 cells
|
Homo sapiens
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR H306A mutant expressed in COS7 cells
|
Homo sapiens
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR H306E mutant expressed in COS7 cells
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR F309L mutant expressed in COS-7 cells
|
Homo sapiens
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR F309Q mutant expressed in COS7 cells
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR F313L mutant expressed in COS7 cells
|
Homo sapiens
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [125I]-His5, D-Tyr6]GnRH from GnRHR F272L mutant expressed in COS7 cells
|
Homo sapiens
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Displacement of [His5, D-Tyr6]GnRH from GnRHR Y290L mutant expressed in COS7 cells
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.
Year : 2006
Volume : 49
Issue : 21
First Page : 6170
Last Page : 6176
Authors : Betz SF, Lio FM, Gao Y, Reinhart GJ, Guo Z, Mesleh MF, Zhu YF, Struthers RS.
Abstract : We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
|
Binding affinity at human GnRH receptor
|
Homo sapiens
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Non-peptide gonadotropin-releasing hormone receptor antagonists.
Year : 2008
Volume : 51
Issue : 12
First Page : 3331
Last Page : 3348
Authors : Betz SF, Zhu YF, Chen C, Struthers RS.
|
Binding affinity at monkey GnRH receptor
|
Macaca mulatta
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Non-peptide gonadotropin-releasing hormone receptor antagonists.
Year : 2008
Volume : 51
Issue : 12
First Page : 3331
Last Page : 3348
Authors : Betz SF, Zhu YF, Chen C, Struthers RS.
|
Binding affinity at cynomolgus monkey GnRH receptor expressed in CHO cells
|
Macaca fascicularis
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Non-peptide gonadotropin-releasing hormone receptor antagonists.
Year : 2008
Volume : 51
Issue : 12
First Page : 3331
Last Page : 3348
Authors : Betz SF, Zhu YF, Chen C, Struthers RS.
|
Activity at cynomolgus monkey GnRH receptor expressed in CHO cells assessed as inhibition of arachidonic acid release
|
Macaca fascicularis
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Non-peptide gonadotropin-releasing hormone receptor antagonists.
Year : 2008
Volume : 51
Issue : 12
First Page : 3331
Last Page : 3348
Authors : Betz SF, Zhu YF, Chen C, Struthers RS.
|
Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter
|
Homo sapiens
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
Year : 2011
Volume : 54
Issue : 14
First Page : 4998
Last Page : 5012
Authors : Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T.
Abstract : We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.
|
Inhibition of human CYP3A4 assessed as conversion of testosterone to 6beta-hydroxytestosterone at 10 uM after 30 mins by HPLC analysis
|
Homo sapiens
|
36.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
Year : 2011
Volume : 54
Issue : 14
First Page : 4998
Last Page : 5012
Authors : Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T.
Abstract : We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.
|
Antagonist activity at human GnRH receptor expressed in CHO cells assessed as inhibition of GnRH-induced arachidonic acid release using [5,6,8,9,11,12,14,15-3H]arachidonic acid preincubated for 15 mins measured after 45 mins by scintillation counting
|
Homo sapiens
|
0.06
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
Year : 2011
Volume : 54
Issue : 14
First Page : 4998
Last Page : 5012
Authors : Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T.
Abstract : We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.
|
Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter in presence of 40% fetal bovine serum
|
Homo sapiens
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
Year : 2011
Volume : 54
Issue : 14
First Page : 4998
Last Page : 5012
Authors : Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T.
Abstract : We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.
|
Antagonist activity at human GnRH receptor expressed in CHO cells assessed as inhibition of GnRH-induced arachidonic acid release using [5,6,8,9,11,12,14,15-3H]arachidonic acid preincubated for 15 mins measured after 45 mins by scintillation counting in presence of 40% fetal bovine serum
|
Homo sapiens
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
Year : 2011
Volume : 54
Issue : 14
First Page : 4998
Last Page : 5012
Authors : Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T.
Abstract : We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.
|
Displacement of [125I]leuprorelin from monkey GnRH receptor expressed in CHO cells after 60 mins by X-ray counter in presence of 40% fetal bovine serum
|
Macaca mulatta
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
Year : 2011
Volume : 54
Issue : 14
First Page : 4998
Last Page : 5012
Authors : Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T.
Abstract : We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.
|
Displacement of [125I]leuprorelin from rat GnRH receptor expressed in CHO cells after 60 mins by X-ray counter in presence of 40% fetal bovine serum
|
Rattus norvegicus
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
Year : 2011
Volume : 54
Issue : 14
First Page : 4998
Last Page : 5012
Authors : Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T.
Abstract : We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.
|
Antagonist activity at human GnRH receptor expressed in CHO cells assessed as inhibition of GnRH-induced arachidonic acid release using [5,6,8,9,11,12,14,15-3H]arachidonic acid preincubated for 15 mins measured after 45 mins by scintillation counting in presence of 40% human serum
|
Homo sapiens
|
270.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
Year : 2011
Volume : 54
Issue : 14
First Page : 4998
Last Page : 5012
Authors : Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T.
Abstract : We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.
