|
Antagonist dissociation constant in rat vas deferens, number of determinations => 3.
|
Rattus norvegicus
|
9.12
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
Year : 2000
Volume : 43
Issue : 8
First Page : 1586
Last Page : 1603
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I.
Abstract : In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
|
Antagonist dissociation constant in dog prostate, number of determinations => 3.
|
Canis lupus familiaris
|
36.31
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
Year : 2000
Volume : 43
Issue : 8
First Page : 1586
Last Page : 1603
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I.
Abstract : In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
|
Antagonist dissociation constant in rat spleen, number of determinations => 3.
|
Rattus norvegicus
|
2.512
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
Year : 2000
Volume : 43
Issue : 8
First Page : 1586
Last Page : 1603
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I.
Abstract : In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
|
In vitro binding affinity using [3H]prazosin as radioligand against adrenoceptor alpha 1A
|
None
|
0.82
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
Year : 2000
Volume : 43
Issue : 8
First Page : 1586
Last Page : 1603
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I.
Abstract : In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
|
In vitro binding affinity using [3H]prazosin as radioligand against adrenoceptor alpha 1b expressed in LTK cell
|
Cricetulus griseus
|
0.69
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
Year : 2000
Volume : 43
Issue : 8
First Page : 1586
Last Page : 1603
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I.
Abstract : In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
|
In vitro binding affinity using [3H]prazosin as radioligand against adrenoceptor alpha 1d expressed in LTK cell
|
None
|
1.01
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
Year : 2000
Volume : 43
Issue : 8
First Page : 1586
Last Page : 1603
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I.
Abstract : In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
|
In vitro antagonism against Alpha-1B adrenergic receptor using phenylephrine (PE) challenge in rat spleen
|
None
|
2.512
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e] isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4 (1H,3H)-dione (A-131701): a uroselective alpha 1A adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 20
First Page : 3141
Last Page : 3143
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Drizin I, Elmore SW, Ehrlich PP, Lebold SA, Tietje K, Sippy KB, Wendt MD, Plata DJ, Plagge F, Buckner SA, Brune ME, Hancock AA, Kerwin JF.
|
In vitro antagonistic activity against alpha-1B receptor in rat spleen.
|
Rattus norvegicus
|
2.512
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.
Year : 2001
Volume : 44
Issue : 12
First Page : 1971
Last Page : 1985
Authors : Meyer MD, Altenbach RJ, Bai H, Basha FZ, Carroll WA, Kerwin JF, Lebold SA, Lee E, Pratt JK, Sippy KB, Tietje K, Wendt MD, Brune ME, Buckner SA, Hancock AA, Drizin I.
Abstract : In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
|
Ability to displace [3H]prazosin from cloned human Alpha-1D adrenergic receptor
|
None
|
3.7
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of alpha 1a-adrenergic receptor antagonists based on the L-type Ca2+ channel antagonist niguldipine.
Year : 1995
Volume : 38
Issue : 10
First Page : 1579
Last Page : 1581
Authors : Wetzel JM, Miao SW, Forray C, Borden LA, Branchek TA, Gluchowski C.
|
Binding affinity against human adrenergic receptor subtype Alpha-1D adrenergic receptor using [3H]prazosin as radioligand
|
None
|
0.85
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e] isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4 (1H,3H)-dione (A-131701): a uroselective alpha 1A adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 20
First Page : 3141
Last Page : 3143
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Drizin I, Elmore SW, Ehrlich PP, Lebold SA, Tietje K, Sippy KB, Wendt MD, Plata DJ, Plagge F, Buckner SA, Brune ME, Hancock AA, Kerwin JF.
|
Compound was tested for its binding affinity utilizing cloned receptor binding assays by using [125 I]HEAT as radioligand to the human Alpha-1D adrenergic receptor
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6, 7-dimethoxyquinazoline (L-765,314): a potent and selective alpha1b adrenergic receptor antagonist.
Year : 1998
Volume : 41
Issue : 8
First Page : 1205
Last Page : 1208
Authors : Patane MA, Scott AL, Broten TP, Chang RS, Ransom RW, DiSalvo J, Forray C, Bock MG.
|
In vitro binding affinity against Alpha-1D adrenergic receptor of human liver microsomes.
|
None
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones.
Year : 1999
Volume : 42
Issue : 23
First Page : 4764
Last Page : 4777
Authors : Nagarathnam D, Miao SW, Lagu B, Chiu G, Fang J, Murali Dhar TG, Zhang J, Tyagarajan S, Marzabadi MR, Zhang F, Wong WC, Sun W, Tian D, Wetzel JM, Forray C, Chang RS, Broten TP, Ransom RW, Schorn TW, Chen TB, O'Malley S, Kling P, Schneck K, Bendesky R, Harrell CM.
Abstract : Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.
|
In vitro binding affinity against Alpha-1D adrenergic receptor of human liver microsomes.
|
None
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains.
Year : 1999
Volume : 42
Issue : 23
First Page : 4794
Last Page : 4803
Authors : Lagu B, Tian D, Nagarathnam D, Marzabadi MR, Wong WC, Miao SW, Zhang F, Sun W, Chiu G, Fang J, Forray C, Chang RS, Ransom RW, Chen TB, O'Malley S, Zhang K, Vyas KP, Gluchowski C.
Abstract : Dihydropyrimidinones, such as 1, represent a novel class of alpha(1a) adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the mu-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the mu-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the mu-opioid receptor.
|
Binding affinity against Alpha-1D adrenergic receptor, from human clones.
|
Homo sapiens
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity was tested on human Alpha-1D adrenergic receptor
|
None
|
3.981
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacological options in the treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 9
First Page : 1293
Last Page : 1315
Authors : Kenny B, Ballard S, Blagg J, Fox D.
|
Binding affinity determined by displacement of [3H]prazosin from alpha-1D adrenergic receptor
|
None
|
3.467
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.
Year : 1998
Volume : 41
Issue : 14
First Page : 2643
Last Page : 2650
Authors : Wong WC, Chiu G, Wetzel JM, Marzabadi MR, Nagarathnam D, Wang D, Fang J, Miao SW, Hong X, Forray C, Vaysse PJ, Branchek TA, Gluchowski C, Tang R, Lepor H.
Abstract : A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.
|
Compound was evaluated for its ability to displace [125I]HEAT binding from rat Alpha-1D adrenergic receptor
|
None
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6, 7-dimethoxyquinazoline (L-765,314): a potent and selective alpha1b adrenergic receptor antagonist.
Year : 1998
Volume : 41
Issue : 8
First Page : 1205
Last Page : 1208
Authors : Patane MA, Scott AL, Broten TP, Chang RS, Ransom RW, DiSalvo J, Forray C, Bock MG.
|
Binding affinity against Alpha-1D adrenergic receptor, from rat clones.
|
Rattus norvegicus
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
In vitro antagonism against Alpha-1D adrenergic receptor using phenylephrine (PE) challenge in rat aorta
|
None
|
2.239
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e] isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4 (1H,3H)-dione (A-131701): a uroselective alpha 1A adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 20
First Page : 3141
Last Page : 3143
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Drizin I, Elmore SW, Ehrlich PP, Lebold SA, Tietje K, Sippy KB, Wendt MD, Plata DJ, Plagge F, Buckner SA, Brune ME, Hancock AA, Kerwin JF.
|
Compound was evaluated for its affinity for Alpha-1a adrenergic receptor in dog aorta preparations
|
Canis lupus familiaris
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-alkylated saccharins as selective alpha-1a adrenergic receptor antagonists.
Year : 1998
Volume : 8
Issue : 18
First Page : 2467
Last Page : 2472
Authors : Nerenberg JB, Erb JM, Thompson WJ, Lee HY, Guare JP, Munson PM, Bergman JM, Huff JR, Broten TP, Chang RS, Chen TB, O'Malley S, Schorn TW, Scott AL.
Abstract : Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.
|
Compound was evaluated for its affinity for Alpha-1a adrenergic receptor in dog prostate tissue preparations
|
Canis lupus familiaris
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-alkylated saccharins as selective alpha-1a adrenergic receptor antagonists.
Year : 1998
Volume : 8
Issue : 18
First Page : 2467
Last Page : 2472
Authors : Nerenberg JB, Erb JM, Thompson WJ, Lee HY, Guare JP, Munson PM, Bergman JM, Huff JR, Broten TP, Chang RS, Chen TB, O'Malley S, Schorn TW, Scott AL.
Abstract : Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.
|
Ability to displace beta ([125I]-iodo-4-hydroxyphenyl)-ethylaminomethyl tetralone from human Alpha-1a adrenergic receptor stably expressed in Chinese Hamster Ovary (CHO) cells
|
None
|
4.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-alkylated saccharins as selective alpha-1a adrenergic receptor antagonists.
Year : 1998
Volume : 8
Issue : 18
First Page : 2467
Last Page : 2472
Authors : Nerenberg JB, Erb JM, Thompson WJ, Lee HY, Guare JP, Munson PM, Bergman JM, Huff JR, Broten TP, Chang RS, Chen TB, O'Malley S, Schorn TW, Scott AL.
Abstract : Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.
|
Compound was evaluated for its affinity for Alpha-1a adrenergic receptor in human aorta preparations
|
None
|
2.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-alkylated saccharins as selective alpha-1a adrenergic receptor antagonists.
Year : 1998
Volume : 8
Issue : 18
First Page : 2467
Last Page : 2472
Authors : Nerenberg JB, Erb JM, Thompson WJ, Lee HY, Guare JP, Munson PM, Bergman JM, Huff JR, Broten TP, Chang RS, Chen TB, O'Malley S, Schorn TW, Scott AL.
Abstract : Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.
|
Compound was evaluated for its affinity for Alpha-1a adrenergic receptor in human prostate tissue preparations
|
None
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-alkylated saccharins as selective alpha-1a adrenergic receptor antagonists.
Year : 1998
Volume : 8
Issue : 18
First Page : 2467
Last Page : 2472
Authors : Nerenberg JB, Erb JM, Thompson WJ, Lee HY, Guare JP, Munson PM, Bergman JM, Huff JR, Broten TP, Chang RS, Chen TB, O'Malley S, Schorn TW, Scott AL.
Abstract : Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.
|
Ability to displace beta ([125I]-iodo-4-hydroxyphenyl)-ethylaminomethyl tetralone from human cloned Alpha-1b adrenergic receptor stably expressed in LM cells
|
None
|
1.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-alkylated saccharins as selective alpha-1a adrenergic receptor antagonists.
Year : 1998
Volume : 8
Issue : 18
First Page : 2467
Last Page : 2472
Authors : Nerenberg JB, Erb JM, Thompson WJ, Lee HY, Guare JP, Munson PM, Bergman JM, Huff JR, Broten TP, Chang RS, Chen TB, O'Malley S, Schorn TW, Scott AL.
Abstract : Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.
|
Ability to displace beta ([125I]-iodo-4-hydroxyphenyl) ethylamino methyl tetralone from human cloned Alpha-1d adrenergic receptor stably expressed in HEK cells.
|
None
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-alkylated saccharins as selective alpha-1a adrenergic receptor antagonists.
Year : 1998
Volume : 8
Issue : 18
First Page : 2467
Last Page : 2472
Authors : Nerenberg JB, Erb JM, Thompson WJ, Lee HY, Guare JP, Munson PM, Bergman JM, Huff JR, Broten TP, Chang RS, Chen TB, O'Malley S, Schorn TW, Scott AL.
Abstract : Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.
|
Ability to displace [3H]rauwolscine from cloned human Alpha-2A adrenergic receptor
|
None
|
550.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of alpha 1a-adrenergic receptor antagonists based on the L-type Ca2+ channel antagonist niguldipine.
Year : 1995
Volume : 38
Issue : 10
First Page : 1579
Last Page : 1581
Authors : Wetzel JM, Miao SW, Forray C, Borden LA, Branchek TA, Gluchowski C.
|
Binding affinity determined by displacement of [3H]rauwolscine from alpha-2A adrenergic receptor
|
None
|
549.54
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.
Year : 1998
Volume : 41
Issue : 14
First Page : 2643
Last Page : 2650
Authors : Wong WC, Chiu G, Wetzel JM, Marzabadi MR, Nagarathnam D, Wang D, Fang J, Miao SW, Hong X, Forray C, Vaysse PJ, Branchek TA, Gluchowski C, Tang R, Lepor H.
Abstract : A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.
|
pA2 for Alpha-1 adrenergic receptor from human prostate.
|
None
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacological options in the treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 9
First Page : 1293
Last Page : 1315
Authors : Kenny B, Ballard S, Blagg J, Fox D.
|
Activity against Alpha-1 adrenergic receptor subtypes of human prostate tissue
|
None
|
25.12
nM
|
|
Journal : J. Med. Chem.
Title : N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.
Year : 1997
Volume : 40
Issue : 17
First Page : 2674
Last Page : 2687
Authors : Elworthy TR, Ford AP, Bantle GW, Morgans DJ, Ozer RS, Palmer WS, Repke DB, Romero M, Sandoval L, Sjogren EB, Talamás FX, Vazquez A, Wu H, Arredondo NF, Blue DR, DeSousa A, Gross LM, Kava MS, Lesnick JD, Vimont RL, Williams TJ, Zhu QM, Pfister JR, Clarke DE.
Abstract : Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
|
Ability to displace [3H]rauwolscine from cloned human Alpha-2B adrenergic receptor
|
None
|
26.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of alpha 1a-adrenergic receptor antagonists based on the L-type Ca2+ channel antagonist niguldipine.
Year : 1995
Volume : 38
Issue : 10
First Page : 1579
Last Page : 1581
Authors : Wetzel JM, Miao SW, Forray C, Borden LA, Branchek TA, Gluchowski C.
|
Binding affinity against Alpha-2B adrenergic receptor from human clones.
|
Homo sapiens
|
418.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity determined by displacement of [3H]rauwolscine from alpha-2B adrenergic receptor
|
None
|
30.9
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.
Year : 1998
Volume : 41
Issue : 14
First Page : 2643
Last Page : 2650
Authors : Wong WC, Chiu G, Wetzel JM, Marzabadi MR, Nagarathnam D, Wang D, Fang J, Miao SW, Hong X, Forray C, Vaysse PJ, Branchek TA, Gluchowski C, Tang R, Lepor H.
Abstract : A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.
|
Binding affinity against rat Alpha-2B adrenergic receptor using [3H]rauwolscine as radioligand
|
None
|
7.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e] isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4 (1H,3H)-dione (A-131701): a uroselective alpha 1A adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 20
First Page : 3141
Last Page : 3143
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Drizin I, Elmore SW, Ehrlich PP, Lebold SA, Tietje K, Sippy KB, Wendt MD, Plata DJ, Plagge F, Buckner SA, Brune ME, Hancock AA, Kerwin JF.
|
Ability to displace [3H]rauwolscine from cloned human Alpha-2C adrenergic receptor
|
None
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of alpha 1a-adrenergic receptor antagonists based on the L-type Ca2+ channel antagonist niguldipine.
Year : 1995
Volume : 38
Issue : 10
First Page : 1579
Last Page : 1581
Authors : Wetzel JM, Miao SW, Forray C, Borden LA, Branchek TA, Gluchowski C.
|
Binding affinity against human Alpha-2C adrenergic receptor using [3H]rauwolscine as radioligand
|
None
|
78.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e] isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4 (1H,3H)-dione (A-131701): a uroselective alpha 1A adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 20
First Page : 3141
Last Page : 3143
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Drizin I, Elmore SW, Ehrlich PP, Lebold SA, Tietje K, Sippy KB, Wendt MD, Plata DJ, Plagge F, Buckner SA, Brune ME, Hancock AA, Kerwin JF.
|
The compound was tested for binding affinity against alpha-2C-adrenoceptor, from human clones.
|
None
|
213.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity against Alpha-1A adrenergic receptor from bovine clone
|
Bos taurus
|
26.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
In vitro for the displacement of [3H]prazosin binding to bovine Alpha-1A adrenergic receptor
|
None
|
2.512
nM
|
|
Journal : J. Med. Chem.
Title : N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.
Year : 1997
Volume : 40
Issue : 17
First Page : 2674
Last Page : 2687
Authors : Elworthy TR, Ford AP, Bantle GW, Morgans DJ, Ozer RS, Palmer WS, Repke DB, Romero M, Sandoval L, Sjogren EB, Talamás FX, Vazquez A, Wu H, Arredondo NF, Blue DR, DeSousa A, Gross LM, Kava MS, Lesnick JD, Vimont RL, Williams TJ, Zhu QM, Pfister JR, Clarke DE.
Abstract : Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
|
In vitro antagonism against Alpha-1A adrenergic receptor using phenylephrine (PE) challenge in dog prostate
|
Canis lupus familiaris
|
36.31
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e] isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4 (1H,3H)-dione (A-131701): a uroselective alpha 1A adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 20
First Page : 3141
Last Page : 3143
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Drizin I, Elmore SW, Ehrlich PP, Lebold SA, Tietje K, Sippy KB, Wendt MD, Plata DJ, Plagge F, Buckner SA, Brune ME, Hancock AA, Kerwin JF.
|
In vitro antagonistic activity against alpha-1A receptor in dog prostate.
|
Canis lupus familiaris
|
36.31
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.
Year : 2001
Volume : 44
Issue : 12
First Page : 1971
Last Page : 1985
Authors : Meyer MD, Altenbach RJ, Bai H, Basha FZ, Carroll WA, Kerwin JF, Lebold SA, Lee E, Pratt JK, Sippy KB, Tietje K, Wendt MD, Brune ME, Buckner SA, Hancock AA, Drizin I.
Abstract : In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
|
Ability to displace [3H]prazosin from cloned human Alpha-1A adrenergic receptor
|
None
|
6.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of alpha 1a-adrenergic receptor antagonists based on the L-type Ca2+ channel antagonist niguldipine.
Year : 1995
Volume : 38
Issue : 10
First Page : 1579
Last Page : 1581
Authors : Wetzel JM, Miao SW, Forray C, Borden LA, Branchek TA, Gluchowski C.
|
Binding affinity against human adrenergic receptor subtype Alpha-1A adrenergic receptor using [3H]prazosin as radioligand
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e] isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4 (1H,3H)-dione (A-131701): a uroselective alpha 1A adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 20
First Page : 3141
Last Page : 3143
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Drizin I, Elmore SW, Ehrlich PP, Lebold SA, Tietje K, Sippy KB, Wendt MD, Plata DJ, Plagge F, Buckner SA, Brune ME, Hancock AA, Kerwin JF.
|
Binding affinity assayed by displacement of [3H]rauwolscine from human alpha-2C adrenergic receptor
|
None
|
223.87
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.
Year : 1998
Volume : 41
Issue : 14
First Page : 2643
Last Page : 2650
Authors : Wong WC, Chiu G, Wetzel JM, Marzabadi MR, Nagarathnam D, Wang D, Fang J, Miao SW, Hong X, Forray C, Vaysse PJ, Branchek TA, Gluchowski C, Tang R, Lepor H.
Abstract : A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.
|
Compound was tested for its binding affinity utilizing cloned receptor binding assays by using [125 I]HEAT as radioligand to the human Alpha-1A adrenergic receptor
|
None
|
4.2
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6, 7-dimethoxyquinazoline (L-765,314): a potent and selective alpha1b adrenergic receptor antagonist.
Year : 1998
Volume : 41
Issue : 8
First Page : 1205
Last Page : 1208
Authors : Patane MA, Scott AL, Broten TP, Chang RS, Ransom RW, DiSalvo J, Forray C, Bock MG.
|
In vitro binding affinity radioligand
|
None
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones.
Year : 1999
Volume : 42
Issue : 23
First Page : 4764
Last Page : 4777
Authors : Nagarathnam D, Miao SW, Lagu B, Chiu G, Fang J, Murali Dhar TG, Zhang J, Tyagarajan S, Marzabadi MR, Zhang F, Wong WC, Sun W, Tian D, Wetzel JM, Forray C, Chang RS, Broten TP, Ransom RW, Schorn TW, Chen TB, O'Malley S, Kling P, Schneck K, Bendesky R, Harrell CM.
Abstract : Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.
|
In vitro binding affinity against Alpha-1A adrenergic receptor of human liver microsomes.
|
None
|
6.9
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones.
Year : 1999
Volume : 42
Issue : 23
First Page : 4764
Last Page : 4777
Authors : Nagarathnam D, Miao SW, Lagu B, Chiu G, Fang J, Murali Dhar TG, Zhang J, Tyagarajan S, Marzabadi MR, Zhang F, Wong WC, Sun W, Tian D, Wetzel JM, Forray C, Chang RS, Broten TP, Ransom RW, Schorn TW, Chen TB, O'Malley S, Kling P, Schneck K, Bendesky R, Harrell CM.
Abstract : Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.
|
In vitro binding affinity against alpha-1A adrenergic receptor of human liver microsomes
|
None
|
6.9
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety.
Year : 1999
Volume : 42
Issue : 23
First Page : 4778
Last Page : 4793
Authors : Murali Dhar TG, Nagarathnam D, Marzabadi MR, Lagu B, Wong WC, Chiu G, Tyagarajan S, Miao SW, Zhang F, Sun W, Tian D, Shen Q, Zhang J, Wetzel JM, Forray C, Chang RS, Broten TP, Schorn TW, Chen TB, O'Malley S, Ransom R, Schneck K, Bendesky R, Harrell CM, Vyas KP.
Abstract : We have previously described compound 1a as a high-affinity subtype selective alpha(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a mu-opioid agonist, 4-methoxycarbonyl-4-phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to mu-opioid activity. Modification of the linker gave several compounds with good alpha(1a) binding affinity (K(i) = < 1 nM) and selectivity (>300-fold over alpha(1b) and alpha(1d)). In vitro analysis in the microsomal assay revealed these modifications did not significantly affect N-dealkylation and the formation of the piperidine 3. The second approach, however, yielded several piperidine replacements for 3, which did not show significant mu-opioid activity. Several of these compounds maintained good affinity at the alpha(1a) adrenoceptor and selectivity over alpha(1b) and alpha(1d). For example, the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the mu-opioid receptor (IC(50) > 30 microM vs 3 microM for 3). Compounds (+)-73 and (+)-83 were subjected to detailed in vitro and in vivo characterization. Both these compounds, in addition to their excellent selectivity (>880-fold) over alpha(1b) and alpha(1d), also showed good selectivity over several other recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional potency in isolated human prostate tissues, with K(b)s comparable to their in vitro alpha(1a) binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs, similar to 1a.
|
In vitro binding affinity against Alpha-1A adrenergic receptor of human liver microsomes.
|
None
|
6.9
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains.
Year : 1999
Volume : 42
Issue : 23
First Page : 4794
Last Page : 4803
Authors : Lagu B, Tian D, Nagarathnam D, Marzabadi MR, Wong WC, Miao SW, Zhang F, Sun W, Chiu G, Fang J, Forray C, Chang RS, Ransom RW, Chen TB, O'Malley S, Zhang K, Vyas KP, Gluchowski C.
Abstract : Dihydropyrimidinones, such as 1, represent a novel class of alpha(1a) adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the mu-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the mu-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the mu-opioid receptor.
|
Binding affinity against Alpha-1A adrenergic receptor from human clone
|
Homo sapiens
|
7.3
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity was tested on human Alpha-1A adrenergic receptor
|
None
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacological options in the treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 9
First Page : 1293
Last Page : 1315
Authors : Kenny B, Ballard S, Blagg J, Fox D.
|
Binding affinity determined by displacement of [3H]prazosin from alpha-1A adrenergic receptor
|
None
|
6.918
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.
Year : 1998
Volume : 41
Issue : 14
First Page : 2643
Last Page : 2650
Authors : Wong WC, Chiu G, Wetzel JM, Marzabadi MR, Nagarathnam D, Wang D, Fang J, Miao SW, Hong X, Forray C, Vaysse PJ, Branchek TA, Gluchowski C, Tang R, Lepor H.
Abstract : A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.
|
Compound was evaluated for its ability to displace [125I]HEAT binding from rat Alpha-1A adrenergic receptor
|
None
|
3.9
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6, 7-dimethoxyquinazoline (L-765,314): a potent and selective alpha1b adrenergic receptor antagonist.
Year : 1998
Volume : 41
Issue : 8
First Page : 1205
Last Page : 1208
Authors : Patane MA, Scott AL, Broten TP, Chang RS, Ransom RW, DiSalvo J, Forray C, Bock MG.
|
In vitro antagonism against Alpha-1A adrenergic receptor using phenylephrine (PE) challenge in rat vas deferens
|
None
|
9.12
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e] isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4 (1H,3H)-dione (A-131701): a uroselective alpha 1A adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 20
First Page : 3141
Last Page : 3143
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Drizin I, Elmore SW, Ehrlich PP, Lebold SA, Tietje K, Sippy KB, Wendt MD, Plata DJ, Plagge F, Buckner SA, Brune ME, Hancock AA, Kerwin JF.
|
In vitro antagonistic activity towards alpha-1A adrenergic receptor in rat vas deferens
|
Rattus norvegicus
|
9.12
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.
Year : 2001
Volume : 44
Issue : 12
First Page : 1971
Last Page : 1985
Authors : Meyer MD, Altenbach RJ, Bai H, Basha FZ, Carroll WA, Kerwin JF, Lebold SA, Lee E, Pratt JK, Sippy KB, Tietje K, Wendt MD, Brune ME, Buckner SA, Hancock AA, Drizin I.
Abstract : In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
|
Antagonistic activity against alpha 1A/1L receptor was assessed in a rabbit bladder neck functional assay
|
Oryctolagus cuniculus
|
19.95
nM
|
|
Journal : J. Med. Chem.
Title : N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.
Year : 1997
Volume : 40
Issue : 17
First Page : 2674
Last Page : 2687
Authors : Elworthy TR, Ford AP, Bantle GW, Morgans DJ, Ozer RS, Palmer WS, Repke DB, Romero M, Sandoval L, Sjogren EB, Talamás FX, Vazquez A, Wu H, Arredondo NF, Blue DR, DeSousa A, Gross LM, Kava MS, Lesnick JD, Vimont RL, Williams TJ, Zhu QM, Pfister JR, Clarke DE.
Abstract : Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
|
Binding affinity against Alpha-1B adrenergic receptor from hamster clones.
|
hamster
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Ability to displace [3H]prazosin from cloned human Alpha-1B adrenergic receptor
|
None
|
2.6
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of alpha 1a-adrenergic receptor antagonists based on the L-type Ca2+ channel antagonist niguldipine.
Year : 1995
Volume : 38
Issue : 10
First Page : 1579
Last Page : 1581
Authors : Wetzel JM, Miao SW, Forray C, Borden LA, Branchek TA, Gluchowski C.
|
Binding affinity against human adrenergic receptor subtype Alpha-1B adrenergic receptor using [3H]prazosin as radioligand
|
None
|
2.68
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e] isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4 (1H,3H)-dione (A-131701): a uroselective alpha 1A adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 20
First Page : 3141
Last Page : 3143
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Drizin I, Elmore SW, Ehrlich PP, Lebold SA, Tietje K, Sippy KB, Wendt MD, Plata DJ, Plagge F, Buckner SA, Brune ME, Hancock AA, Kerwin JF.
|
Compound was tested for its binding affinity utilizing cloned receptor binding assays by using [125 I]HEAT as radioligand to the human Alpha-1B adrenergic receptor
|
None
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6, 7-dimethoxyquinazoline (L-765,314): a potent and selective alpha1b adrenergic receptor antagonist.
Year : 1998
Volume : 41
Issue : 8
First Page : 1205
Last Page : 1208
Authors : Patane MA, Scott AL, Broten TP, Chang RS, Ransom RW, DiSalvo J, Forray C, Bock MG.
|
In vitro binding affinity against Alpha-1B adrenergic receptor of human liver microsomes.
|
None
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones.
Year : 1999
Volume : 42
Issue : 23
First Page : 4764
Last Page : 4777
Authors : Nagarathnam D, Miao SW, Lagu B, Chiu G, Fang J, Murali Dhar TG, Zhang J, Tyagarajan S, Marzabadi MR, Zhang F, Wong WC, Sun W, Tian D, Wetzel JM, Forray C, Chang RS, Broten TP, Ransom RW, Schorn TW, Chen TB, O'Malley S, Kling P, Schneck K, Bendesky R, Harrell CM.
Abstract : Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.
|
In vitro binding affinity against Alpha-1B adrenergic receptor of human liver microsomes.
|
None
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains.
Year : 1999
Volume : 42
Issue : 23
First Page : 4794
Last Page : 4803
Authors : Lagu B, Tian D, Nagarathnam D, Marzabadi MR, Wong WC, Miao SW, Zhang F, Sun W, Chiu G, Fang J, Forray C, Chang RS, Ransom RW, Chen TB, O'Malley S, Zhang K, Vyas KP, Gluchowski C.
Abstract : Dihydropyrimidinones, such as 1, represent a novel class of alpha(1a) adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the mu-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the mu-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the mu-opioid receptor.
|
Binding affinity against Alpha-1B adrenergic receptor from human clone
|
Homo sapiens
|
2.2
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity was tested on human Alpha-1B adrenergic receptor
|
None
|
2.512
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacological options in the treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 9
First Page : 1293
Last Page : 1315
Authors : Kenny B, Ballard S, Blagg J, Fox D.
|
Binding affinity determined by displacement of [3H]prazosin from alpha-1B adrenergic receptor
|
None
|
1.95
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.
Year : 1998
Volume : 41
Issue : 14
First Page : 2643
Last Page : 2650
Authors : Wong WC, Chiu G, Wetzel JM, Marzabadi MR, Nagarathnam D, Wang D, Fang J, Miao SW, Hong X, Forray C, Vaysse PJ, Branchek TA, Gluchowski C, Tang R, Lepor H.
Abstract : A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.
|
Compound was evaluated for its ability to displace [125I]HEAT binding from rat Alpha-1B adrenergic receptor
|
None
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6, 7-dimethoxyquinazoline (L-765,314): a potent and selective alpha1b adrenergic receptor antagonist.
Year : 1998
Volume : 41
Issue : 8
First Page : 1205
Last Page : 1208
Authors : Patane MA, Scott AL, Broten TP, Chang RS, Ransom RW, DiSalvo J, Forray C, Bock MG.
|
In vivo antagonist dissociation constant in intaraurethral pressure model in dogs.
|
Canis lupus familiaris
|
95.5
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.
Year : 2001
Volume : 44
Issue : 12
First Page : 1971
Last Page : 1985
Authors : Meyer MD, Altenbach RJ, Bai H, Basha FZ, Carroll WA, Kerwin JF, Lebold SA, Lee E, Pratt JK, Sippy KB, Tietje K, Wendt MD, Brune ME, Buckner SA, Hancock AA, Drizin I.
Abstract : In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
|
Compound was tested for efficacy in a challenge intraurethral pressure (IUP) model using aged anesthetized dogs
|
Canis lupus familiaris
|
95.5
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e] isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4 (1H,3H)-dione (A-131701): a uroselective alpha 1A adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 20
First Page : 3141
Last Page : 3143
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Drizin I, Elmore SW, Ehrlich PP, Lebold SA, Tietje K, Sippy KB, Wendt MD, Plata DJ, Plagge F, Buckner SA, Brune ME, Hancock AA, Kerwin JF.
|
Antagonist activity at alpha-1L-adrenoceptor in human prostate assessed as inhibition of noradrenaline-mediated contraction
|
Homo sapiens
|
0.1585
nM
|
|
Journal : Drug Metab. Dispos.
Title : Impact of physicochemical and structural properties on the pharmacokinetics of a series of alpha1L-adrenoceptor antagonists.
Year : 2007
Volume : 35
Issue : 8
First Page : 1435
Last Page : 1445
Authors : Betts A, Atkinson F, Gardner I, Fox D, Webster R, Beaumont K, Morgan P.
Abstract : A rational drug discovery process was initiated to design a potent and prostate-selective alpha1(L)-adrenoceptor antagonist with pharmacokinetic properties suitable for once a day administration after oral dosing, for the treatment of benign prostatic hyperplasia. Two series of compounds based on a quinoline or quinazoline template were identified with appropriate pharmacology. A series of high molecular weight cations with high hydrogen-bonding potential had extensive in vivo clearance, despite demonstrating metabolic stability. Studies in the isolated perfused rat liver and fresh rat hepatocytes indicated that active transport protein-mediated hepatobiliary elimination is an efficient clearance process for these compounds. A reduction in molecular weight and hydrogen-bonding potential resulted in a second series of compounds with in vivo hepatic clearance predictable from in vitro metabolic clearance. Initially, lipophilicity was reduced within this second series to reduce metabolic clearance and increase elimination half-life. However, this strategy also resulted in a concomitant reduction in volume of distribution and a negligible effect on prolonging half-life. An alternative strategy was to increase the intrinsic metabolic stability of the molecule by careful structural modifications while maintaining lipophilicity. Replacement of the metabolically vulnerable morpholine side chain resulted in identification of UK-338,003, (N-[2-(4-amino-6,7-dimethoxy-5-pyridin-2-yl-quinazolin-2-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-methanesulfonamide), which fulfilled the objectives of the discovery program with suitable pharmacology (human prostate alpha1(L) pA(2) of 9.2 with 25-fold selectivity over rat aorta alpha1(D)) and sufficiently long elimination half-life in human volunteers (11-17 h) for once a day administration.
|
Antagonist activity at alpha-1-adrenoceptor in rat aorta assessed as inhibition of noradrenaline-mediated contraction
|
Rattus norvegicus
|
0.1
nM
|
|
Journal : Drug Metab. Dispos.
Title : Impact of physicochemical and structural properties on the pharmacokinetics of a series of alpha1L-adrenoceptor antagonists.
Year : 2007
Volume : 35
Issue : 8
First Page : 1435
Last Page : 1445
Authors : Betts A, Atkinson F, Gardner I, Fox D, Webster R, Beaumont K, Morgan P.
Abstract : A rational drug discovery process was initiated to design a potent and prostate-selective alpha1(L)-adrenoceptor antagonist with pharmacokinetic properties suitable for once a day administration after oral dosing, for the treatment of benign prostatic hyperplasia. Two series of compounds based on a quinoline or quinazoline template were identified with appropriate pharmacology. A series of high molecular weight cations with high hydrogen-bonding potential had extensive in vivo clearance, despite demonstrating metabolic stability. Studies in the isolated perfused rat liver and fresh rat hepatocytes indicated that active transport protein-mediated hepatobiliary elimination is an efficient clearance process for these compounds. A reduction in molecular weight and hydrogen-bonding potential resulted in a second series of compounds with in vivo hepatic clearance predictable from in vitro metabolic clearance. Initially, lipophilicity was reduced within this second series to reduce metabolic clearance and increase elimination half-life. However, this strategy also resulted in a concomitant reduction in volume of distribution and a negligible effect on prolonging half-life. An alternative strategy was to increase the intrinsic metabolic stability of the molecule by careful structural modifications while maintaining lipophilicity. Replacement of the metabolically vulnerable morpholine side chain resulted in identification of UK-338,003, (N-[2-(4-amino-6,7-dimethoxy-5-pyridin-2-yl-quinazolin-2-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-methanesulfonamide), which fulfilled the objectives of the discovery program with suitable pharmacology (human prostate alpha1(L) pA(2) of 9.2 with 25-fold selectivity over rat aorta alpha1(D)) and sufficiently long elimination half-life in human volunteers (11-17 h) for once a day administration.
|
Inhibition of prazosin uptake at transport-P transporter protein in mouse GT1-1 cells at 100 uM relative to desipramine
|
Mus musculus
|
41.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Molecular features of the prazosin molecule required for activation of Transport-P.
Year : 2008
Volume : 16
Issue : 15
First Page : 7254
Last Page : 7263
Authors : da Silva JF, Walters M, Al-Damluji S, Ganellin CR.
Abstract : Closely related structural analogues of prazosin have been synthesised and tested for inhibition and activation of Transport-P in order to identify the structural features of the prazosin molecule that appear to be necessary for activation of Transport-P. So far, all the compounds tested are less active than prazosin. It is shown that the structure of prazosin appears to be very specific for the activation. Only quinazolines have been found to activate, and the presence of the 6,7-dimethoxy and 4-amino groups appears to be critically important.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
77.0
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
24.0
nM
|
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
9.592
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
6.025
nM
|
|
DRUGMATRIX: Alpha-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
3.335
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
17.0
nM
|
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
8.363
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
428.0
nM
|
|
DRUGMATRIX: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
195.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
878.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Imidazoline I2, Central radioligand binding (ligand: [3H] Idazoxan)
|
Rattus norvegicus
|
846.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Antagonist activity at angiotensin-2 receptor in Wistar rat endothelium denuded thoracic aorta assessed as inhibition of angiotensin 2-induced contraction preincubated for 30 mins prior to angiotensin 2-challenge
|
Rattus norvegicus
|
407.38
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism.
Year : 2013
Volume : 23
Issue : 13
First Page : 3959
Last Page : 3966
Authors : Yadav MR, Naik PP, Gandhi HP, Chauhan BS, Giridhar R.
Abstract : Multiple-targeted ligands can have certain advantages for the management of hypertension which has multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic disorders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type α1-blockers and AII-antagonists it was planned to develop dual α1- and AII-antagonists. Five series of quinazoline derivatives were synthesized and evaluated as dual α1- and AII-antagonists on rat aortic strips for the blockade of known α1- and AII-agonist mediated contractions. Many compounds showed balanced activity on both the receptors but compound (22) was found to be the most active derivative having higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound (22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed a new light on the structural requirements for both α1- as well as AII-receptor antagonists.
|
Antagonist activity at alpha1-adrenergic receptor in Wistar rat endothelium denuded thoracic aorta assessed as inhibition of phenylephrine-induced contraction preincubated for 30 mins prior to phenylephrine-challenge
|
Rattus norvegicus
|
2.239
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism.
Year : 2013
Volume : 23
Issue : 13
First Page : 3959
Last Page : 3966
Authors : Yadav MR, Naik PP, Gandhi HP, Chauhan BS, Giridhar R.
Abstract : Multiple-targeted ligands can have certain advantages for the management of hypertension which has multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic disorders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type α1-blockers and AII-antagonists it was planned to develop dual α1- and AII-antagonists. Five series of quinazoline derivatives were synthesized and evaluated as dual α1- and AII-antagonists on rat aortic strips for the blockade of known α1- and AII-agonist mediated contractions. Many compounds showed balanced activity on both the receptors but compound (22) was found to be the most active derivative having higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound (22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed a new light on the structural requirements for both α1- as well as AII-receptor antagonists.
|
Antagonist activity at alpha-1A adrenergic receptor (unknown origin) incubated for 30 mins prior to agonist addition measured after 5 hrs by CCF4-AM staining-based cellular assay
|
Homo sapiens
|
51.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : α-Adrenoceptor antagonistic and hypotensive properties of novel arylpiperazine derivatives of pyrrolidin-2-one.
Year : 2015
Volume : 23
Issue : 9
First Page : 2104
Last Page : 2111
Authors : Zaręba P, Dudek M, Lustyk K, Siwek A, Starowicz G, Bednarski M, Nowiński L, Raźny K, Sapa J, Malawska B, Kulig K.
Abstract : This study focused on a series of pyrrolidin-2-one derivatives connected via two or four methylene units to arylpiperazine fragment. The compounds obtained for α₁- and α₂-adrenoceptors were assessed. The compound with highest affinity for the α₁-adrenoceptors was 1-{4-[4-(2-chloro-phenyl)-piperazin-1-yl]-butyl}-pyrrolidin-2-one (10 h) with pKi=7.30. Compound with pKi (α₁) ⩾6.44 were evaluated in functional bioassays for intrinsic activity at α₁A- and α₁B-adrenoceptors. All compounds tested were antagonists of the α₁B-adrenoceptors. Additionally, compounds 10e and 10h were α₁A-adrenoceptors antagonist. The dual α₁A-/α₁B-adrenoceptors antagonists, compounds 10e and 10h were also tested in vivo for their hypotensive activity in rats. These compounds, when dosed of 1.0 mg/kg iv in normotensive, anesthetized rats, significantly decreased systolic and diastolic pressure and their hypotensive effects lasted for longer than one hour.
|
Antagonist activity at alpha-1B adrenergic receptor (unknown origin) incubated for 30 mins prior to agonist addition measured after 5 hrs by CCF4-AM staining-based cellular assay
|
Homo sapiens
|
0.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : α-Adrenoceptor antagonistic and hypotensive properties of novel arylpiperazine derivatives of pyrrolidin-2-one.
Year : 2015
Volume : 23
Issue : 9
First Page : 2104
Last Page : 2111
Authors : Zaręba P, Dudek M, Lustyk K, Siwek A, Starowicz G, Bednarski M, Nowiński L, Raźny K, Sapa J, Malawska B, Kulig K.
Abstract : This study focused on a series of pyrrolidin-2-one derivatives connected via two or four methylene units to arylpiperazine fragment. The compounds obtained for α₁- and α₂-adrenoceptors were assessed. The compound with highest affinity for the α₁-adrenoceptors was 1-{4-[4-(2-chloro-phenyl)-piperazin-1-yl]-butyl}-pyrrolidin-2-one (10 h) with pKi=7.30. Compound with pKi (α₁) ⩾6.44 were evaluated in functional bioassays for intrinsic activity at α₁A- and α₁B-adrenoceptors. All compounds tested were antagonists of the α₁B-adrenoceptors. Additionally, compounds 10e and 10h were α₁A-adrenoceptors antagonist. The dual α₁A-/α₁B-adrenoceptors antagonists, compounds 10e and 10h were also tested in vivo for their hypotensive activity in rats. These compounds, when dosed of 1.0 mg/kg iv in normotensive, anesthetized rats, significantly decreased systolic and diastolic pressure and their hypotensive effects lasted for longer than one hour.
|
Antagonist activity at Sprague-Dawley rat prostatic vas deferens adrenergic alpha-1A receptor after 20 mins
|
Rattus norvegicus
|
12.59
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel naftopidil-related derivatives and their biological effects as alpha1-adrenoceptors antagonists and antiproliferative agents.
Year : 2015
Volume : 96
First Page : 83
Last Page : 91
Authors : Huang J, He F, Huang M, Liu X, Xiong Y, Huang Y, Zhu L, Yang Y, Xu X, Yuan M.
Abstract : Eleven novel naftopidil-related compounds that contain amide and indole groups were designed and synthesized. The biological effects of these compounds on three α1-adrenoceptor subtypes and cancerous human prostate cell lines (PC-3, DU-145, and LNCaP) were determined. Compounds 2, 3, 5, 11, and 12 exhibited an α1-adrenoceptor antagonistic activity, whereas compounds 9, 10, and 12 displayed moderate antiproliferative activities. Compound 3 exhibited a significant α(1D/1A) blocking activity in isolated rat tissues (97.7- and 64.6-fold selective for α(1D) and α(1A) compared with α(1B)) but not a relevant cytotoxic activity. Compound 12 demonstrated a potent and selective α(1D/1A) antagonistic activity (47.9- and 19.1-fold for α(1D) and α(1A) compared with α1B) and a potent antiproliferative activity in PC-3 cells (IC50 = 15.70 μM). Further testing confirmed that compound 12 inhibited the growth of PC-3 cells by inducing apoptosis and G0/G1 cell cycle arrest, which was mediated by α1-adrenoceptor. Therefore, compound 12 is a potential multipotent agent that can act as an effective α1-adrenoceptor subtype antagonist for treating benign prostatic hyperplasia and a preventive medication against human prostate cancer.
|
Antagonist activity at Sprague-Dawley rat spleen adrenergic alpha-1B receptor after 20 mins
|
Rattus norvegicus
|
2.57
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel naftopidil-related derivatives and their biological effects as alpha1-adrenoceptors antagonists and antiproliferative agents.
Year : 2015
Volume : 96
First Page : 83
Last Page : 91
Authors : Huang J, He F, Huang M, Liu X, Xiong Y, Huang Y, Zhu L, Yang Y, Xu X, Yuan M.
Abstract : Eleven novel naftopidil-related compounds that contain amide and indole groups were designed and synthesized. The biological effects of these compounds on three α1-adrenoceptor subtypes and cancerous human prostate cell lines (PC-3, DU-145, and LNCaP) were determined. Compounds 2, 3, 5, 11, and 12 exhibited an α1-adrenoceptor antagonistic activity, whereas compounds 9, 10, and 12 displayed moderate antiproliferative activities. Compound 3 exhibited a significant α(1D/1A) blocking activity in isolated rat tissues (97.7- and 64.6-fold selective for α(1D) and α(1A) compared with α(1B)) but not a relevant cytotoxic activity. Compound 12 demonstrated a potent and selective α(1D/1A) antagonistic activity (47.9- and 19.1-fold for α(1D) and α(1A) compared with α1B) and a potent antiproliferative activity in PC-3 cells (IC50 = 15.70 μM). Further testing confirmed that compound 12 inhibited the growth of PC-3 cells by inducing apoptosis and G0/G1 cell cycle arrest, which was mediated by α1-adrenoceptor. Therefore, compound 12 is a potential multipotent agent that can act as an effective α1-adrenoceptor subtype antagonist for treating benign prostatic hyperplasia and a preventive medication against human prostate cancer.
|
Antagonist activity at Sprague-Dawley rat thoracic aorta adrenergic alpha-1D receptor after 20 mins
|
Rattus norvegicus
|
1.479
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel naftopidil-related derivatives and their biological effects as alpha1-adrenoceptors antagonists and antiproliferative agents.
Year : 2015
Volume : 96
First Page : 83
Last Page : 91
Authors : Huang J, He F, Huang M, Liu X, Xiong Y, Huang Y, Zhu L, Yang Y, Xu X, Yuan M.
Abstract : Eleven novel naftopidil-related compounds that contain amide and indole groups were designed and synthesized. The biological effects of these compounds on three α1-adrenoceptor subtypes and cancerous human prostate cell lines (PC-3, DU-145, and LNCaP) were determined. Compounds 2, 3, 5, 11, and 12 exhibited an α1-adrenoceptor antagonistic activity, whereas compounds 9, 10, and 12 displayed moderate antiproliferative activities. Compound 3 exhibited a significant α(1D/1A) blocking activity in isolated rat tissues (97.7- and 64.6-fold selective for α(1D) and α(1A) compared with α(1B)) but not a relevant cytotoxic activity. Compound 12 demonstrated a potent and selective α(1D/1A) antagonistic activity (47.9- and 19.1-fold for α(1D) and α(1A) compared with α1B) and a potent antiproliferative activity in PC-3 cells (IC50 = 15.70 μM). Further testing confirmed that compound 12 inhibited the growth of PC-3 cells by inducing apoptosis and G0/G1 cell cycle arrest, which was mediated by α1-adrenoceptor. Therefore, compound 12 is a potential multipotent agent that can act as an effective α1-adrenoceptor subtype antagonist for treating benign prostatic hyperplasia and a preventive medication against human prostate cancer.
|
Intrinsic activity at alpha1A adrenergic receptor (unknown origin) assessed as inhibition of agonist induced effect preincubated for 30 mins followed by agonist addition measured after 5 hrs in presence of CCF4-AM by cell based beta lactamase reporter gene assay
|
Homo sapiens
|
51.89
nM
|
|
Journal : Bioorg Med Chem
Title : Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α1-adrenergic receptor antagonist with uro-selective activity.
Year : 2016
Volume : 24
Issue : 21
First Page : 5582
Last Page : 5591
Authors : Rak A, Canale V, Marciniec K, Żmudzki P, Kotańska M, Knutelska J, Siwek A, Stachowicz G, Bednarski M, Nowiński L, Zygmunt M, Zajdel P, Sapa J.
Abstract : A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α1-adrenoceptor antagonists with uroselective profile. Biological evaluation for α1- and α2-adrenorecepor showed that tested compounds 13-37 displayed high-to-moderate affinity for the α1-adrenoceptor (Ki=34-348nM) and moderate selectivity over α2-receptor subtype. Compounds with highest affinity and selectivity for α1-adrenoceptor were evaluated in vitro for their intrinsic activity toward α1A- and α1B-adrenoceptor subtypes. All compounds behaved as antagonists at both α1-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α1A-subtype. Among them, N-{1-[2-(2-methoxyphenoxy)ethyl]piperidin-4-yl}isoquinoline-4-sulfonamide (25) and 3-chloro-2-fluoro-N-{[1-(2-(2-isopropoxyphenoxy)ethyl)piperidin-4-yl]methyl}benzene sulfonamide (34) displayed the highest preference to α1A-adrenoceptor. Finally, compounds 25 and 34 (2-5mg/kg, iv), in contrast to tamsulosin (1-2mg/kg, iv), did not significantly decrease systolic and diastolic blood pressure in normotensive anesthetized rats to determine their influence on blood pressure.
|
Intrinsic activity at human alpha1B adrenergic receptor expressed in CHOK1 cells co-expressing aequorin assessed as inhibition of agonist induced calcium mobilization preincubated for 15 mins followed by agonist addition measured for 20 secs in presence of coelenterazine H by luminescence assay
|
Homo sapiens
|
1.73
nM
|
|
Journal : Bioorg Med Chem
Title : Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α1-adrenergic receptor antagonist with uro-selective activity.
Year : 2016
Volume : 24
Issue : 21
First Page : 5582
Last Page : 5591
Authors : Rak A, Canale V, Marciniec K, Żmudzki P, Kotańska M, Knutelska J, Siwek A, Stachowicz G, Bednarski M, Nowiński L, Zygmunt M, Zajdel P, Sapa J.
Abstract : A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α1-adrenoceptor antagonists with uroselective profile. Biological evaluation for α1- and α2-adrenorecepor showed that tested compounds 13-37 displayed high-to-moderate affinity for the α1-adrenoceptor (Ki=34-348nM) and moderate selectivity over α2-receptor subtype. Compounds with highest affinity and selectivity for α1-adrenoceptor were evaluated in vitro for their intrinsic activity toward α1A- and α1B-adrenoceptor subtypes. All compounds behaved as antagonists at both α1-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α1A-subtype. Among them, N-{1-[2-(2-methoxyphenoxy)ethyl]piperidin-4-yl}isoquinoline-4-sulfonamide (25) and 3-chloro-2-fluoro-N-{[1-(2-(2-isopropoxyphenoxy)ethyl)piperidin-4-yl]methyl}benzene sulfonamide (34) displayed the highest preference to α1A-adrenoceptor. Finally, compounds 25 and 34 (2-5mg/kg, iv), in contrast to tamsulosin (1-2mg/kg, iv), did not significantly decrease systolic and diastolic blood pressure in normotensive anesthetized rats to determine their influence on blood pressure.
|
Antagonist activity at alpha1A-adrenoreceptor in Sprague-Dawley rat vas deferens assessed as relaxation of (-)-noradrenaline-induced contractile response
|
Rattus norvegicus
|
12.59
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes.
Year : 2018
Volume : 28
Issue : 4
First Page : 547
Last Page : 551
Authors : Huang JJ, Zhang ZH, He F, Liu XW, Xu XJ, Dai LJ, Liu QM, Yuan M.
Abstract : α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.
|
Antagonist activity at alpha1B-adrenoreceptor in Sprague-Dawley rat spleen assessed as relaxation of (-)-noradrenaline-induced contractile response
|
Rattus norvegicus
|
2.57
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes.
Year : 2018
Volume : 28
Issue : 4
First Page : 547
Last Page : 551
Authors : Huang JJ, Zhang ZH, He F, Liu XW, Xu XJ, Dai LJ, Liu QM, Yuan M.
Abstract : α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.
|
Antagonist activity at alpha1D-adrenoreceptor in Sprague-Dawley rat thoracic aorta assessed as relaxation of (-)-noradrenaline-induced contractile response
|
Rattus norvegicus
|
1.479
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes.
Year : 2018
Volume : 28
Issue : 4
First Page : 547
Last Page : 551
Authors : Huang JJ, Zhang ZH, He F, Liu XW, Xu XJ, Dai LJ, Liu QM, Yuan M.
Abstract : α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.
|
Antagonist activity at alpha1D-adrenoreceptor in Sprague-Dawley rat thoracic aorta assessed as relaxation of phenylephrine-induced contractile response
|
Rattus norvegicus
|
2.239
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes.
Year : 2018
Volume : 28
Issue : 4
First Page : 547
Last Page : 551
Authors : Huang JJ, Zhang ZH, He F, Liu XW, Xu XJ, Dai LJ, Liu QM, Yuan M.
Abstract : α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.
|
Antagonist activity at alpha1A-adrenoreceptor in Sprague-Dawley rat vas deferens assessed as relaxation of phenylephrine-induced contractile response
|
Rattus norvegicus
|
9.12
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes.
Year : 2018
Volume : 28
Issue : 4
First Page : 547
Last Page : 551
Authors : Huang JJ, Zhang ZH, He F, Liu XW, Xu XJ, Dai LJ, Liu QM, Yuan M.
Abstract : α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.
|
Antagonist activity at alpha1B-adrenoreceptor in Sprague-Dawley rat spleen assessed as relaxation of phenylephrine-induced contractile response
|
Rattus norvegicus
|
2.512
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes.
Year : 2018
Volume : 28
Issue : 4
First Page : 547
Last Page : 551
Authors : Huang JJ, Zhang ZH, He F, Liu XW, Xu XJ, Dai LJ, Liu QM, Yuan M.
Abstract : α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
8.19
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-0.53
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
3.6
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
7.31
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
18.79
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
3.05
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
0.02
%
|
|
