|
EP4 agonist potency utilizing a stable clone of pSV40-EP4 transfected into HEK293 cells expressing EP4 receptor
|
None
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a potent and selective agonist of the prostaglandin EP4 receptor.
Year : 2003
Volume : 13
Issue : 6
First Page : 1129
Last Page : 1132
Authors : Billot X, Chateauneuf A, Chauret N, Denis D, Greig G, Mathieu MC, Metters KM, Slipetz DM, Young RN.
Abstract : Analogues of PGE(2) wherein the hydroxycyclopentanone ring has been replaced by a lactam have been prepared and evaluated as ligands for the EP(4) receptor. An optimized compound (19a) shows high potency and agonist efficacy at the EP(4) receptor and is highly selective over the other seven known prostaglandin receptors.
|
Inhibitory activity against human EP4 receptor expressed in HEK293 ebna cells
|
None
|
0.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a potent and selective agonist of the prostaglandin EP4 receptor.
Year : 2003
Volume : 13
Issue : 6
First Page : 1129
Last Page : 1132
Authors : Billot X, Chateauneuf A, Chauret N, Denis D, Greig G, Mathieu MC, Metters KM, Slipetz DM, Young RN.
Abstract : Analogues of PGE(2) wherein the hydroxycyclopentanone ring has been replaced by a lactam have been prepared and evaluated as ligands for the EP(4) receptor. An optimized compound (19a) shows high potency and agonist efficacy at the EP(4) receptor and is highly selective over the other seven known prostaglandin receptors.
|
Cytoprotective activity in rat when administered 0.25 mg/kg perorally (Ethyl alcohol as necrotic agent)
|
Rattus norvegicus
|
89.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of 3-substituted imidazo[1,2-a]pyridines as antiulcer agents.
Year : 1989
Volume : 32
Issue : 9
First Page : 2204
Last Page : 2210
Authors : Starrett JE, Montzka TA, Crosswell AR, Cavanagh RL.
Abstract : New imidazo[1,2-a]pyridines substituted at the 3-position have been synthesized as potential antisecretory and cytoprotective antiulcer agents. The synthetic routes began with cyclization of aminopyridines 5a,b and chloro ketones 6a,b to give imidazo[1,2-a]pyridines 7-9. The side chain at the 3-position was elaborated to give primary amines 12a-c, which were treated with either butoxyaminocyclobutenedione 13 or methoxyaminothiadiazole 1-oxide (15) to give 14a,b and 16a-c, respectively. Thiadiazole 1-oxides 16a-c were converted to thiadiazoles 19a-c in a two-step process which involved extrusion of the sulfoxide in 16a-c to afford diimidamides 17a-c, which were subsequently treated with thiobisphthalimide (18). None of the compounds displayed significant antisecretory activity in the gastric fistula rat model, but several demonstrated good cytoprotective properties in both the EtOH and HCl models. 8-(Benzyloxy)-3-[1-[[2-[(4-amino-1,2,5-thiadiazol-3- yl)amino]ethyl]thio]ethyl]-2-methylimidazo[1,2-a]pyridine (19c) showed comparable cytoprotective activity to SCH-28080 (4).
|
Cytoprotective activity in rats when administered 0.10 mg/kg perorally per orally (Hydrochloric acid as necrotic agent)
|
Rattus norvegicus
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of 3-substituted imidazo[1,2-a]pyridines as antiulcer agents.
Year : 1989
Volume : 32
Issue : 9
First Page : 2204
Last Page : 2210
Authors : Starrett JE, Montzka TA, Crosswell AR, Cavanagh RL.
Abstract : New imidazo[1,2-a]pyridines substituted at the 3-position have been synthesized as potential antisecretory and cytoprotective antiulcer agents. The synthetic routes began with cyclization of aminopyridines 5a,b and chloro ketones 6a,b to give imidazo[1,2-a]pyridines 7-9. The side chain at the 3-position was elaborated to give primary amines 12a-c, which were treated with either butoxyaminocyclobutenedione 13 or methoxyaminothiadiazole 1-oxide (15) to give 14a,b and 16a-c, respectively. Thiadiazole 1-oxides 16a-c were converted to thiadiazoles 19a-c in a two-step process which involved extrusion of the sulfoxide in 16a-c to afford diimidamides 17a-c, which were subsequently treated with thiobisphthalimide (18). None of the compounds displayed significant antisecretory activity in the gastric fistula rat model, but several demonstrated good cytoprotective properties in both the EtOH and HCl models. 8-(Benzyloxy)-3-[1-[[2-[(4-amino-1,2,5-thiadiazol-3- yl)amino]ethyl]thio]ethyl]-2-methylimidazo[1,2-a]pyridine (19c) showed comparable cytoprotective activity to SCH-28080 (4).
|
Displacement of [3H]PGE2 from human EP1 receptor expressed in HEK293 cells
|
Homo sapiens
|
9.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel prostaglandin analogs of PGE2 as potent and selective EP2 and EP4 receptor agonists.
Year : 2007
Volume : 17
Issue : 15
First Page : 4323
Last Page : 4327
Authors : Xiao Y, Araldi GL, Zhao Z, Brugger N, Karra S, Fischer D, Palmer E.
Abstract : Analogs of PGE(2) with introduction of diene groups at the omega-side chain have been synthesized and evaluated for their binding affinity for EP(2) and EP(4) receptors. An optimized analog (compound 9b) showed high potency and selectivity for the EP(4) receptor over other known receptors.
|
Displacement of [3H]PGE2 from human EP2 receptor expressed in HEK293 cells
|
Homo sapiens
|
4.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel prostaglandin analogs of PGE2 as potent and selective EP2 and EP4 receptor agonists.
Year : 2007
Volume : 17
Issue : 15
First Page : 4323
Last Page : 4327
Authors : Xiao Y, Araldi GL, Zhao Z, Brugger N, Karra S, Fischer D, Palmer E.
Abstract : Analogs of PGE(2) with introduction of diene groups at the omega-side chain have been synthesized and evaluated for their binding affinity for EP(2) and EP(4) receptors. An optimized analog (compound 9b) showed high potency and selectivity for the EP(4) receptor over other known receptors.
|
Displacement of [3H]PGE2 from human EP3 receptor expressed in HEK293 cells
|
Homo sapiens
|
0.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel prostaglandin analogs of PGE2 as potent and selective EP2 and EP4 receptor agonists.
Year : 2007
Volume : 17
Issue : 15
First Page : 4323
Last Page : 4327
Authors : Xiao Y, Araldi GL, Zhao Z, Brugger N, Karra S, Fischer D, Palmer E.
Abstract : Analogs of PGE(2) with introduction of diene groups at the omega-side chain have been synthesized and evaluated for their binding affinity for EP(2) and EP(4) receptors. An optimized analog (compound 9b) showed high potency and selectivity for the EP(4) receptor over other known receptors.
|
Displacement of [3H]PGE2 from human EP4 receptor expressed in HEK293 cells
|
Homo sapiens
|
0.79
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel prostaglandin analogs of PGE2 as potent and selective EP2 and EP4 receptor agonists.
Year : 2007
Volume : 17
Issue : 15
First Page : 4323
Last Page : 4327
Authors : Xiao Y, Araldi GL, Zhao Z, Brugger N, Karra S, Fischer D, Palmer E.
Abstract : Analogs of PGE(2) with introduction of diene groups at the omega-side chain have been synthesized and evaluated for their binding affinity for EP(2) and EP(4) receptors. An optimized analog (compound 9b) showed high potency and selectivity for the EP(4) receptor over other known receptors.
|
Binding affinity at human prostaglandin EP2 receptor
|
Homo sapiens
|
4.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of novel pyrazolidinone analogs of PGE2 as EP2 and EP4 receptors agonists.
Year : 2007
Volume : 17
Issue : 23
First Page : 6572
Last Page : 6575
Authors : Zhao Z, Araldi GL, Xiao Y, Reddy AP, Liao Y, Karra S, Brugger N, Fischer D, Palmer E.
Abstract : Replacement of the hydroxy cyclopentanone ring in PGE(2) with chemically more stable heterocyclic rings and substitution of the unsaturated alpha-alkenyl chain with a metabolically more stable phenethyl chain led to the development of potent and selective analogs of PGE(2). Compound 10f showed the highest potency and selectivity for EP(4) the receptor.
|
Binding affinity at human prostaglandin EP4 receptor
|
Homo sapiens
|
0.79
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of novel pyrazolidinone analogs of PGE2 as EP2 and EP4 receptors agonists.
Year : 2007
Volume : 17
Issue : 23
First Page : 6572
Last Page : 6575
Authors : Zhao Z, Araldi GL, Xiao Y, Reddy AP, Liao Y, Karra S, Brugger N, Fischer D, Palmer E.
Abstract : Replacement of the hydroxy cyclopentanone ring in PGE(2) with chemically more stable heterocyclic rings and substitution of the unsaturated alpha-alkenyl chain with a metabolically more stable phenethyl chain led to the development of potent and selective analogs of PGE(2). Compound 10f showed the highest potency and selectivity for EP(4) the receptor.
|
Displacement of [3H]PGE2 from human EP2 receptor
|
Homo sapiens
|
4.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of a gamma-lactam as a highly selective EP2 and EP4 receptor agonist.
Year : 2008
Volume : 18
Issue : 2
First Page : 821
Last Page : 824
Authors : Xiao Y, Araldi GL, Zhao Z, Reddy A, Karra S, Brugger N, Fischer D, Palmer E, Bao B, McKenna SD.
Abstract : Gamma-lactam analogs (2) of EP(4) receptor agonists were identified by substitution of the pyrazolidinone ring (1) with a pyrrolidinone ring. Several compounds (such as 2a, 2h) with high potency, selectivity and acceptable PK profiles were discovered. These were assessed in animal models of ovulation induction and bronchoconstriction.
|
Displacement of [3H]PGE4 from human EP4 receptor
|
Homo sapiens
|
0.79
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of a gamma-lactam as a highly selective EP2 and EP4 receptor agonist.
Year : 2008
Volume : 18
Issue : 2
First Page : 821
Last Page : 824
Authors : Xiao Y, Araldi GL, Zhao Z, Reddy A, Karra S, Brugger N, Fischer D, Palmer E, Bao B, McKenna SD.
Abstract : Gamma-lactam analogs (2) of EP(4) receptor agonists were identified by substitution of the pyrazolidinone ring (1) with a pyrrolidinone ring. Several compounds (such as 2a, 2h) with high potency, selectivity and acceptable PK profiles were discovered. These were assessed in animal models of ovulation induction and bronchoconstriction.
|
Agonist activity at human EP4 receptor by cAMP assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of a gamma-lactam as a highly selective EP2 and EP4 receptor agonist.
Year : 2008
Volume : 18
Issue : 2
First Page : 821
Last Page : 824
Authors : Xiao Y, Araldi GL, Zhao Z, Reddy A, Karra S, Brugger N, Fischer D, Palmer E, Bao B, McKenna SD.
Abstract : Gamma-lactam analogs (2) of EP(4) receptor agonists were identified by substitution of the pyrazolidinone ring (1) with a pyrrolidinone ring. Several compounds (such as 2a, 2h) with high potency, selectivity and acceptable PK profiles were discovered. These were assessed in animal models of ovulation induction and bronchoconstriction.
|
Displacement of [3H]PGE2 from human EP1 receptor
|
Homo sapiens
|
9.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of a gamma-lactam as a highly selective EP2 and EP4 receptor agonist.
Year : 2008
Volume : 18
Issue : 2
First Page : 821
Last Page : 824
Authors : Xiao Y, Araldi GL, Zhao Z, Reddy A, Karra S, Brugger N, Fischer D, Palmer E, Bao B, McKenna SD.
Abstract : Gamma-lactam analogs (2) of EP(4) receptor agonists were identified by substitution of the pyrazolidinone ring (1) with a pyrrolidinone ring. Several compounds (such as 2a, 2h) with high potency, selectivity and acceptable PK profiles were discovered. These were assessed in animal models of ovulation induction and bronchoconstriction.
|
Displacement of [3H]PGE2 from human EP3 receptor
|
Homo sapiens
|
0.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of a gamma-lactam as a highly selective EP2 and EP4 receptor agonist.
Year : 2008
Volume : 18
Issue : 2
First Page : 821
Last Page : 824
Authors : Xiao Y, Araldi GL, Zhao Z, Reddy A, Karra S, Brugger N, Fischer D, Palmer E, Bao B, McKenna SD.
Abstract : Gamma-lactam analogs (2) of EP(4) receptor agonists were identified by substitution of the pyrazolidinone ring (1) with a pyrrolidinone ring. Several compounds (such as 2a, 2h) with high potency, selectivity and acceptable PK profiles were discovered. These were assessed in animal models of ovulation induction and bronchoconstriction.
|
Displacement of radiolabeled PGE2 from human prostanoid EP4 receptor
|
Homo sapiens
|
1.9
nM
|
|
Displacement of radiolabeled PGE2 from human prostanoid EP4 receptor
|
Homo sapiens
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia.
Year : 2008
Volume : 51
Issue : 22
First Page : 7094
Last Page : 7098
Authors : Liu H, Altenbach RJ, Carr TL, Chandran P, Hsieh GC, Lewis LG, Manelli AM, Milicic I, Marsh KC, Miller TR, Strakhova MI, Vortherms TA, Wakefield BD, Wetter JM, Witte DG, Honore P, Esbenshade TA, Brioni JD, Cowart MD.
Abstract : cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.
|
Inhibition of rat EP2 receptor expressed in HEK293 cells
|
Rattus norvegicus
|
5.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of CP-533536: an EP2 receptor selective prostaglandin E2 (PGE2) agonist that induces local bone formation.
Year : 2009
Volume : 19
Issue : 7
First Page : 2075
Last Page : 2078
Authors : Cameron KO, Lefker BA, Ke HZ, Li M, Zawistoski MP, Tjoa CM, Wright AS, DeNinno SL, Paralkar VM, Owen TA, Yu L, Thompson DD.
Abstract : Sulfonamides, exemplified by 3a, were identified as highly selective EP(2) agonists. Lead optimization led to the identification of CP-533536, 7f, a potent and selective EP(2) agonist. CP-533536 demonstrated the ability to heal fractures when administered locally as a single dose in rat models of fracture healing.
|
Inhibition of rat EP4 receptor expressed in HEK293 cells
|
Rattus norvegicus
|
2.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of CP-533536: an EP2 receptor selective prostaglandin E2 (PGE2) agonist that induces local bone formation.
Year : 2009
Volume : 19
Issue : 7
First Page : 2075
Last Page : 2078
Authors : Cameron KO, Lefker BA, Ke HZ, Li M, Zawistoski MP, Tjoa CM, Wright AS, DeNinno SL, Paralkar VM, Owen TA, Yu L, Thompson DD.
Abstract : Sulfonamides, exemplified by 3a, were identified as highly selective EP(2) agonists. Lead optimization led to the identification of CP-533536, 7f, a potent and selective EP(2) agonist. CP-533536 demonstrated the ability to heal fractures when administered locally as a single dose in rat models of fracture healing.
|
Agonist activity against rat EP2 receptor expressed in HEK293 cells assessed as stimulation of cAMP release
|
Rattus norvegicus
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of CP-533536: an EP2 receptor selective prostaglandin E2 (PGE2) agonist that induces local bone formation.
Year : 2009
Volume : 19
Issue : 7
First Page : 2075
Last Page : 2078
Authors : Cameron KO, Lefker BA, Ke HZ, Li M, Zawistoski MP, Tjoa CM, Wright AS, DeNinno SL, Paralkar VM, Owen TA, Yu L, Thompson DD.
Abstract : Sulfonamides, exemplified by 3a, were identified as highly selective EP(2) agonists. Lead optimization led to the identification of CP-533536, 7f, a potent and selective EP(2) agonist. CP-533536 demonstrated the ability to heal fractures when administered locally as a single dose in rat models of fracture healing.
|
Agonist activity against rat EP4 receptor expressed in HEK293 cells assessed as stimulation of cAMP release
|
Rattus norvegicus
|
0.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of CP-533536: an EP2 receptor selective prostaglandin E2 (PGE2) agonist that induces local bone formation.
Year : 2009
Volume : 19
Issue : 7
First Page : 2075
Last Page : 2078
Authors : Cameron KO, Lefker BA, Ke HZ, Li M, Zawistoski MP, Tjoa CM, Wright AS, DeNinno SL, Paralkar VM, Owen TA, Yu L, Thompson DD.
Abstract : Sulfonamides, exemplified by 3a, were identified as highly selective EP(2) agonists. Lead optimization led to the identification of CP-533536, 7f, a potent and selective EP(2) agonist. CP-533536 demonstrated the ability to heal fractures when administered locally as a single dose in rat models of fracture healing.
|
Binding affinity to EP1 receptor
|
None
|
1.1
nM
|
|
Journal : J. Med. Chem.
Title : Emerging targets in osteoporosis disease modification.
Year : 2010
Volume : 53
Issue : 11
First Page : 4332
Last Page : 4353
Authors : Allen JG, Fotsch C, Babij P.
|
Binding affinity to EP2 receptor
|
None
|
37.7
nM
|
|
Journal : J. Med. Chem.
Title : Emerging targets in osteoporosis disease modification.
Year : 2010
Volume : 53
Issue : 11
First Page : 4332
Last Page : 4353
Authors : Allen JG, Fotsch C, Babij P.
|
Binding affinity to EP3 receptor
|
None
|
0.94
nM
|
|
Journal : J. Med. Chem.
Title : Emerging targets in osteoporosis disease modification.
Year : 2010
Volume : 53
Issue : 11
First Page : 4332
Last Page : 4353
Authors : Allen JG, Fotsch C, Babij P.
|
Binding affinity to EP4 receptor
|
None
|
9.9
nM
|
|
Journal : J. Med. Chem.
Title : Emerging targets in osteoporosis disease modification.
Year : 2010
Volume : 53
Issue : 11
First Page : 4332
Last Page : 4353
Authors : Allen JG, Fotsch C, Babij P.
|
Displacement of [3H]-PGE2 from mouse EP1 receptor expressed in CHO cells after 20 mins by liquid scintillation counting
|
Mus musculus
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity.
Year : 2012
Volume : 22
Issue : 1
First Page : 396
Last Page : 401
Authors : Kambe T, Maruyama T, Nakano M, Nakai Y, Yoshida T, Matsunaga N, Oida H, Konaka A, Maruyama T, Nakai H, Toda M.
Abstract : A series of γ-lactam prostaglandin E(1) analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K(i) values: mEP2=9.3 nM, mEP4=0.41 nM). A structure-activity relationship study is presented.
|
Displacement of [3H]-PGE2 from mouse EP2 receptor expressed in CHO cells after 60 mins by liquid scintillation counting
|
Mus musculus
|
22.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity.
Year : 2012
Volume : 22
Issue : 1
First Page : 396
Last Page : 401
Authors : Kambe T, Maruyama T, Nakano M, Nakai Y, Yoshida T, Matsunaga N, Oida H, Konaka A, Maruyama T, Nakai H, Toda M.
Abstract : A series of γ-lactam prostaglandin E(1) analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K(i) values: mEP2=9.3 nM, mEP4=0.41 nM). A structure-activity relationship study is presented.
|
Displacement of [3H]-PGE2 from mouse EP3 receptor expressed in CHO cells after 60 mins by liquid scintillation counting
|
Mus musculus
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity.
Year : 2012
Volume : 22
Issue : 1
First Page : 396
Last Page : 401
Authors : Kambe T, Maruyama T, Nakano M, Nakai Y, Yoshida T, Matsunaga N, Oida H, Konaka A, Maruyama T, Nakai H, Toda M.
Abstract : A series of γ-lactam prostaglandin E(1) analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K(i) values: mEP2=9.3 nM, mEP4=0.41 nM). A structure-activity relationship study is presented.
|
Displacement of [3H]-PGE2 from mouse EP4 receptor expressed in CHO cells after 60 mins by liquid scintillation counting
|
Mus musculus
|
3.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity.
Year : 2012
Volume : 22
Issue : 1
First Page : 396
Last Page : 401
Authors : Kambe T, Maruyama T, Nakano M, Nakai Y, Yoshida T, Matsunaga N, Oida H, Konaka A, Maruyama T, Nakai H, Toda M.
Abstract : A series of γ-lactam prostaglandin E(1) analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K(i) values: mEP2=9.3 nM, mEP4=0.41 nM). A structure-activity relationship study is presented.
|
Displacement of [3H]-PGE2 from mouse EP1 receptor expressed in CHO cells after 60 mins by scintillation counting
|
Mus musculus
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.
Year : 2012
Volume : 20
Issue : 7
First Page : 2235
Last Page : 2251
Authors : Kambe T, Maruyama T, Nakai Y, Yoshida H, Oida H, Maruyama T, Abe N, Nishiura A, Nakai H, Toda M.
Abstract : To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.
|
Displacement of [3H]-PGE2 from mouse EP2 receptor expressed in CHO cells after 60 mins by scintillation counting
|
Mus musculus
|
22.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.
Year : 2012
Volume : 20
Issue : 7
First Page : 2235
Last Page : 2251
Authors : Kambe T, Maruyama T, Nakai Y, Yoshida H, Oida H, Maruyama T, Abe N, Nishiura A, Nakai H, Toda M.
Abstract : To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.
|
Displacement of [3H]-PGE2 from mouse EP3 receptor expressed in CHO cells after 60 mins by scintillation counting
|
Mus musculus
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.
Year : 2012
Volume : 20
Issue : 7
First Page : 2235
Last Page : 2251
Authors : Kambe T, Maruyama T, Nakai Y, Yoshida H, Oida H, Maruyama T, Abe N, Nishiura A, Nakai H, Toda M.
Abstract : To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.
|
Displacement of [3H]-PGE2 from mouse EP4 receptor expressed in CHO cells after 60 mins by scintillation counting
|
Mus musculus
|
3.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.
Year : 2012
Volume : 20
Issue : 7
First Page : 2235
Last Page : 2251
Authors : Kambe T, Maruyama T, Nakai Y, Yoshida H, Oida H, Maruyama T, Abe N, Nishiura A, Nakai H, Toda M.
Abstract : To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.
|
Agonist activity at rat EP2 receptor
|
Rattus norvegicus
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.
Year : 2012
Volume : 20
Issue : 7
First Page : 2235
Last Page : 2251
Authors : Kambe T, Maruyama T, Nakai Y, Yoshida H, Oida H, Maruyama T, Abe N, Nishiura A, Nakai H, Toda M.
Abstract : To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.
|
Agonist activity at rat EP4 receptor
|
Rattus norvegicus
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.
Year : 2012
Volume : 20
Issue : 7
First Page : 2235
Last Page : 2251
Authors : Kambe T, Maruyama T, Nakai Y, Yoshida H, Oida H, Maruyama T, Abe N, Nishiura A, Nakai H, Toda M.
Abstract : To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
14.85
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of horse BChE at 2 mg/ml by Ellman's method
|
Equus caballus
|
-2.38
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Binding affinity to human EP2 receptor (unknown origin) by radioligand displacement assay
|
Homo sapiens
|
2.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide stereoisomers as novel positive allosteric modulators of sigma-1 receptor.
Year : 2013
Volume : 21
Issue : 10
First Page : 2764
Last Page : 2771
Authors : Veinberg G, Vorona M, Zvejniece L, Vilskersts R, Vavers E, Liepinsh E, Kazoka H, Belyakov S, Mishnev A, Kuznecovs J, Vikainis S, Orlova N, Lebedev A, Ponomaryov Y, Dambrova M.
Abstract : Novel positive allosteric modulators of sigma-1 receptor represented by 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide enantiomers were synthesised using an asymmetric Michael addition of 2-nitroprop-1-enylbenzene to diethyl malonate. Following the chromatographic separation of the methyl erythro- and threo-4-nitro-3R- and 3S-phenylpentanoate diastereoisomers, target compounds were obtained by their reductive cyclisation into 5-methyl-4-phenylpyrrolidin-2-one enantiomers and the attachment of the acetamide group to the heterocyclic nitrogen. Experiments with electrically stimulated rat vas deference contractions induced by the PRE-084, an agonist of sigma-1 receptor, showed that (4R,5S)- and (4R,5R)-2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamides with an R-configuration at the C-4 chiral centre in the 2-pyrrolidone ring were more effective positive allosteric modulators of sigma-1 receptor than were their optical antipodes.
|
Displacement of [3H]PGE2 from human recombinant prostanoid EP4 receptor in CHEM1 cells after 2 hrs
|
Homo sapiens
|
0.45
nM
|
|
Displacement of [3H]PGE2 from human recombinant prostanoid EP4 receptor in CHEM1 cells after 2 hrs
|
Homo sapiens
|
1.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Displacement of [3H]PGE2 from human recombinant prostanoid EP4 receptor in CHEM1 cells at 10 uM after 2 hrs relative to control
|
Homo sapiens
|
5.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Binding affinity to human prostanoid EP4 receptor by radioligand displacement assay
|
Homo sapiens
|
0.17
nM
|
|
Binding affinity to human prostanoid EP4 receptor by radioligand displacement assay
|
Homo sapiens
|
0.45
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and structure-activity relationship studies in serotonin 5-HT(1A) receptor agonists based on fused pyrrolidone scaffolds.
Year : 2013
Volume : 63
First Page : 85
Last Page : 94
Authors : Cappelli A, Manini M, Valenti S, Castriconi F, Giuliani G, Anzini M, Brogi S, Butini S, Gemma S, Campiani G, Giorgi G, Mennuni L, Lanza M, Giordani A, Caselli G, Letari O, Makovec F.
Abstract : A new class of serotonin 5-HT1A receptor ligands related to NAN-190, buspirone and aripiprazole has been designed using our potent 5-HT3 receptor ligands as templates. The designed pyrrolidone derivatives 10a-n were prepared by means of the straightforward chemistry consisting in the reaction of the appropriate γ-haloester derivatives with the suitable arylpiperazinylalkylamines. The nanomolar 5-HT1A receptor affinity and the agonist-like profile shown by fused pyrrolidone derivatives 10k,m stimulated the rationalization of the interaction with an homology model of the 5-HT1A receptor and the evaluation of their selectivity profiles and the pharmacokinetic properties. Interestingly, the results of the profiling assays suggested for close congeners 10k,m a significantly divergent binding pattern with compound 10m showing an appreciable selectivity for 5-HT1AR.
|
Binding affinity to human prostanoid EP2 receptor by radioligand displacement assay
|
Homo sapiens
|
1.7
nM
|
|
Binding affinity to human prostanoid EP2 receptor by radioligand displacement assay
|
Homo sapiens
|
3.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and structure-activity relationship studies in serotonin 5-HT(1A) receptor agonists based on fused pyrrolidone scaffolds.
Year : 2013
Volume : 63
First Page : 85
Last Page : 94
Authors : Cappelli A, Manini M, Valenti S, Castriconi F, Giuliani G, Anzini M, Brogi S, Butini S, Gemma S, Campiani G, Giorgi G, Mennuni L, Lanza M, Giordani A, Caselli G, Letari O, Makovec F.
Abstract : A new class of serotonin 5-HT1A receptor ligands related to NAN-190, buspirone and aripiprazole has been designed using our potent 5-HT3 receptor ligands as templates. The designed pyrrolidone derivatives 10a-n were prepared by means of the straightforward chemistry consisting in the reaction of the appropriate γ-haloester derivatives with the suitable arylpiperazinylalkylamines. The nanomolar 5-HT1A receptor affinity and the agonist-like profile shown by fused pyrrolidone derivatives 10k,m stimulated the rationalization of the interaction with an homology model of the 5-HT1A receptor and the evaluation of their selectivity profiles and the pharmacokinetic properties. Interestingly, the results of the profiling assays suggested for close congeners 10k,m a significantly divergent binding pattern with compound 10m showing an appreciable selectivity for 5-HT1AR.
|
Binding affinity to EP2 receptor (unknown origin) by competitive binding assay
|
Homo sapiens
|
38.0
nM
|
|
Journal : J. Med. Chem.
Title : Prostanoid receptor EP2 as a therapeutic target.
Year : 2014
Volume : 57
Issue : 11
First Page : 4454
Last Page : 4465
Authors : Ganesh T.
Abstract : Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.
|
Binding affinity to EP1 receptor (unknown origin)
|
Homo sapiens
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Prostanoid receptor EP2 as a therapeutic target.
Year : 2014
Volume : 57
Issue : 11
First Page : 4454
Last Page : 4465
Authors : Ganesh T.
Abstract : Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.
|
Binding affinity to EP3 receptor (unknown origin)
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Prostanoid receptor EP2 as a therapeutic target.
Year : 2014
Volume : 57
Issue : 11
First Page : 4454
Last Page : 4465
Authors : Ganesh T.
Abstract : Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.
|
Binding affinity to EP4 receptor (unknown origin)
|
Homo sapiens
|
3.1
nM
|
|
Journal : J. Med. Chem.
Title : Prostanoid receptor EP2 as a therapeutic target.
Year : 2014
Volume : 57
Issue : 11
First Page : 4454
Last Page : 4465
Authors : Ganesh T.
Abstract : Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.
|
Agonist activity at EP2 receptor (unknown origin) by functional assay
|
Homo sapiens
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Prostanoid receptor EP2 as a therapeutic target.
Year : 2014
Volume : 57
Issue : 11
First Page : 4454
Last Page : 4465
Authors : Ganesh T.
Abstract : Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.
|
Agonist activity at prostanoid IP receptor (unknown origin) by functional assay
|
Homo sapiens
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : Prostanoid receptor EP2 as a therapeutic target.
Year : 2014
Volume : 57
Issue : 11
First Page : 4454
Last Page : 4465
Authors : Ganesh T.
Abstract : Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.
|
Displacement of [3H]PGE2 from human recombinant prostanoid EP2 receptor expressed in HEK293 cells
|
Homo sapiens
|
2.6
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents.
Year : 2016
Volume : 24
Issue : 8
First Page : 1793
Last Page : 1810
Authors : Waszkielewicz AM, Gunia-Krzyżak A, Powroźnik B, Słoczyńska K, Pękala E, Walczak M, Bednarski M, Żesławska E, Nitek W, Marona H.
Abstract : A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(-)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50=12.92 mg/kg b.w. and its rotarod TD50=33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model-the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule.
|
Agonist activity at human EP2 receptor expressed in CHO cells assessed as increase in intracellular cAMP level after 30 mins by HTRF method
|
Homo sapiens
|
1.9
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of G Protein-Biased EP2 Receptor Agonists.
Year : 2016
Volume : 7
Issue : 3
First Page : 306
Last Page : 311
Authors : Ogawa S, Watanabe T, Sugimoto I, Moriyuki K, Goto Y, Yamane S, Watanabe A, Tsuboi K, Kinoshita A, Kigoshi H, Tani K, Maruyama T.
Abstract : To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.
|
Agonist activity at human EP4 receptor expressed in CHO cells assessed as increase in intracellular cAMP level after 30 mins by HTRF method
|
Homo sapiens
|
7.5
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of G Protein-Biased EP2 Receptor Agonists.
Year : 2016
Volume : 7
Issue : 3
First Page : 306
Last Page : 311
Authors : Ogawa S, Watanabe T, Sugimoto I, Moriyuki K, Goto Y, Yamane S, Watanabe A, Tsuboi K, Kinoshita A, Kigoshi H, Tani K, Maruyama T.
Abstract : To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.
|
Agonist activity at human IP receptor expressed in CHO cells assessed as increase in intracellular cAMP level after 30 mins by HTRF method
|
Homo sapiens
|
347.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of G Protein-Biased EP2 Receptor Agonists.
Year : 2016
Volume : 7
Issue : 3
First Page : 306
Last Page : 311
Authors : Ogawa S, Watanabe T, Sugimoto I, Moriyuki K, Goto Y, Yamane S, Watanabe A, Tsuboi K, Kinoshita A, Kigoshi H, Tani K, Maruyama T.
Abstract : To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.
|
Agonist activity at PK2-tagged human EP2 receptor expressed in HEK293 cells assessed as induction of EA-tagged beta-arrestin recruitment incubated for 90 mins by beta-galactosidase reporter gene assay
|
Homo sapiens
|
346.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of G Protein-Biased EP2 Receptor Agonists.
Year : 2016
Volume : 7
Issue : 3
First Page : 306
Last Page : 311
Authors : Ogawa S, Watanabe T, Sugimoto I, Moriyuki K, Goto Y, Yamane S, Watanabe A, Tsuboi K, Kinoshita A, Kigoshi H, Tani K, Maruyama T.
Abstract : To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.
|
Agonist activity at human EP1 receptor expressed in CHO cells assessed as increase in intracellular calcium level by fluorescence based analysis
|
Homo sapiens
|
3.7
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of G Protein-Biased EP2 Receptor Agonists.
Year : 2016
Volume : 7
Issue : 3
First Page : 306
Last Page : 311
Authors : Ogawa S, Watanabe T, Sugimoto I, Moriyuki K, Goto Y, Yamane S, Watanabe A, Tsuboi K, Kinoshita A, Kigoshi H, Tani K, Maruyama T.
Abstract : To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.
|
Agonist activity at human EP3 receptor expressed in CHO cells assessed as increase in intracellular calcium level by fluorescence based analysis
|
Homo sapiens
|
2.5
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of G Protein-Biased EP2 Receptor Agonists.
Year : 2016
Volume : 7
Issue : 3
First Page : 306
Last Page : 311
Authors : Ogawa S, Watanabe T, Sugimoto I, Moriyuki K, Goto Y, Yamane S, Watanabe A, Tsuboi K, Kinoshita A, Kigoshi H, Tani K, Maruyama T.
Abstract : To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.
|
Agonist activity at human FP receptor expressed in human Chem1 cells assessed as increase in intracellular calcium level by fluorescence based analysis
|
Homo sapiens
|
250.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of G Protein-Biased EP2 Receptor Agonists.
Year : 2016
Volume : 7
Issue : 3
First Page : 306
Last Page : 311
Authors : Ogawa S, Watanabe T, Sugimoto I, Moriyuki K, Goto Y, Yamane S, Watanabe A, Tsuboi K, Kinoshita A, Kigoshi H, Tani K, Maruyama T.
Abstract : To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.
|
Displacement of [3H]PGE2 from human recombinant EP2 receptor expressed in HEK293 cells measured after 120 mins by scintillation counting method
|
Homo sapiens
|
2.6
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3.
Year : 2017
Volume : 25
Issue : 2
First Page : 471
Last Page : 482
Authors : Gunia-Krzyżak A, Żelaszczyk D, Rapacz A, Żesławska E, Waszkielewicz AM, Pańczyk K, Słoczyńska K, Pękala E, Nitek W, Filipek B, Marona H.
Abstract : A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50 MES=42.56, ED50 scPTZ=58.38, ED50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED50 MES=53.76, ED50 scPTZ=90.31, ED50 6-Hz 44mA=92.86mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED50 MES=55.58, ED50 scPTZ=102.15, ED50 6-Hz 44mA=51.27mg/kg mice, i.p.). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives.
|
Displacement of [3H]PGE2 from human recombinant EP4 receptor expressed in HEK293 cells measured after 120 mins by scintillation counting method
|
Homo sapiens
|
0.55
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3.
Year : 2017
Volume : 25
Issue : 2
First Page : 471
Last Page : 482
Authors : Gunia-Krzyżak A, Żelaszczyk D, Rapacz A, Żesławska E, Waszkielewicz AM, Pańczyk K, Słoczyńska K, Pękala E, Nitek W, Filipek B, Marona H.
Abstract : A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50 MES=42.56, ED50 scPTZ=58.38, ED50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED50 MES=53.76, ED50 scPTZ=90.31, ED50 6-Hz 44mA=92.86mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED50 MES=55.58, ED50 scPTZ=102.15, ED50 6-Hz 44mA=51.27mg/kg mice, i.p.). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
10.64
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Displacement of [3H]prostaglandin E2 from human EP2 receptor expressed in HEK293 cell membranes after 60 mins by liquid scintillation counting
|
Homo sapiens
|
4.0
nM
|
|
Journal : J Med Chem
Title : Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag Isopropyl.
Year : 2018
Volume : 61
Issue : 15
First Page : 6869
Last Page : 6891
Authors : Iwamura R, Tanaka M, Okanari E, Kirihara T, Odani-Kawabata N, Shams N, Yoneda K.
Abstract : EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chemistry efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag isopropyl (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clinical candidate for the treatment of glaucoma.
|
Displacement of [3H]prostaglandin E2 from recombinant human full length EP1 receptor expressed in Chem-1 cell membranes after 60 mins by liquid scintillation counting
|
Homo sapiens
|
30.0
nM
|
|
Journal : J Med Chem
Title : Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag Isopropyl.
Year : 2018
Volume : 61
Issue : 15
First Page : 6869
Last Page : 6891
Authors : Iwamura R, Tanaka M, Okanari E, Kirihara T, Odani-Kawabata N, Shams N, Yoneda K.
Abstract : EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chemistry efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag isopropyl (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clinical candidate for the treatment of glaucoma.
|
Displacement of [3H]prostaglandin E2 from recombinant human full length EP3 receptor expressed in Chem-1 cell membranes after 60 mins by liquid scintillation counting
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag Isopropyl.
Year : 2018
Volume : 61
Issue : 15
First Page : 6869
Last Page : 6891
Authors : Iwamura R, Tanaka M, Okanari E, Kirihara T, Odani-Kawabata N, Shams N, Yoneda K.
Abstract : EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chemistry efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag isopropyl (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clinical candidate for the treatment of glaucoma.
|
Displacement of [3H]prostaglandin E2 from recombinant human full length EP4 receptor expressed in Chem-1 cell membranes after 60 mins by liquid scintillation counting
|
Homo sapiens
|
5.0
nM
|
|
Journal : J Med Chem
Title : Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag Isopropyl.
Year : 2018
Volume : 61
Issue : 15
First Page : 6869
Last Page : 6891
Authors : Iwamura R, Tanaka M, Okanari E, Kirihara T, Odani-Kawabata N, Shams N, Yoneda K.
Abstract : EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chemistry efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag isopropyl (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clinical candidate for the treatment of glaucoma.
|
Displacement of [3H]PGE2 from human recombinant EP2 receptor expressed in HEK293 cell membranes after 120 mins by liquid scintillation counting method
|
Homo sapiens
|
1.03
nM
|
|
Journal : J Med Chem
Title : Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE<sub>1</sub> Series EP<sub>4</sub> Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE<sub>1</sub> Analog (KMN-159) as a Potent EP<sub>4</sub> Agonist.
Year : 2019
Volume : 62
Issue : 9
First Page : 4731
Last Page : 4741
Authors : Barrett SD, Holt MC, Kramer JB, Germain B, Ho CS, Ciske FL, Kornilov A, Colombo JM, Uzieblo A, O'Malley JP, Owen TA, Stein AJ, Morano MI.
Abstract : A series of small-molecule full agonists of the prostaglandin E<sub>2</sub> type 4 (EP<sub>4</sub>) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.
|
Displacement of [3H]PGE2 from human recombinant EP3 receptor expressed in HEK293 cell membranes after 120 mins by liquid scintillation counting method
|
Homo sapiens
|
2.17
nM
|
|
Journal : J Med Chem
Title : Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE<sub>1</sub> Series EP<sub>4</sub> Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE<sub>1</sub> Analog (KMN-159) as a Potent EP<sub>4</sub> Agonist.
Year : 2019
Volume : 62
Issue : 9
First Page : 4731
Last Page : 4741
Authors : Barrett SD, Holt MC, Kramer JB, Germain B, Ho CS, Ciske FL, Kornilov A, Colombo JM, Uzieblo A, O'Malley JP, Owen TA, Stein AJ, Morano MI.
Abstract : A series of small-molecule full agonists of the prostaglandin E<sub>2</sub> type 4 (EP<sub>4</sub>) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.
|
Displacement of [3H]PGE2 from human recombinant EP4 receptor expressed in HEK293 cell membranes after 120 mins by liquid scintillation counting method
|
Homo sapiens
|
0.11
nM
|
|
Journal : J Med Chem
Title : Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE<sub>1</sub> Series EP<sub>4</sub> Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE<sub>1</sub> Analog (KMN-159) as a Potent EP<sub>4</sub> Agonist.
Year : 2019
Volume : 62
Issue : 9
First Page : 4731
Last Page : 4741
Authors : Barrett SD, Holt MC, Kramer JB, Germain B, Ho CS, Ciske FL, Kornilov A, Colombo JM, Uzieblo A, O'Malley JP, Owen TA, Stein AJ, Morano MI.
Abstract : A series of small-molecule full agonists of the prostaglandin E<sub>2</sub> type 4 (EP<sub>4</sub>) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.
|
Agonist activity at human EP4 receptor expressed in HEK293T/17 cells assessed as increase in intracellular cAMP level incubated for 30 mins by ELISA
|
Homo sapiens
|
0.583
nM
|
|
Journal : J Med Chem
Title : Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE<sub>1</sub> Series EP<sub>4</sub> Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE<sub>1</sub> Analog (KMN-159) as a Potent EP<sub>4</sub> Agonist.
Year : 2019
Volume : 62
Issue : 9
First Page : 4731
Last Page : 4741
Authors : Barrett SD, Holt MC, Kramer JB, Germain B, Ho CS, Ciske FL, Kornilov A, Colombo JM, Uzieblo A, O'Malley JP, Owen TA, Stein AJ, Morano MI.
Abstract : A series of small-molecule full agonists of the prostaglandin E<sub>2</sub> type 4 (EP<sub>4</sub>) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.
|
Agonist activity at human EP2 receptor expressed in HEK293T/17 cells assessed as increase in intracellular cAMP level incubated for 30 mins by ELISA
|
Homo sapiens
|
331.0
nM
|
|
Journal : J Med Chem
Title : Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE<sub>1</sub> Series EP<sub>4</sub> Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE<sub>1</sub> Analog (KMN-159) as a Potent EP<sub>4</sub> Agonist.
Year : 2019
Volume : 62
Issue : 9
First Page : 4731
Last Page : 4741
Authors : Barrett SD, Holt MC, Kramer JB, Germain B, Ho CS, Ciske FL, Kornilov A, Colombo JM, Uzieblo A, O'Malley JP, Owen TA, Stein AJ, Morano MI.
Abstract : A series of small-molecule full agonists of the prostaglandin E<sub>2</sub> type 4 (EP<sub>4</sub>) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.
|
Agonist activity at human EP4 receptor expressed in HEK293T/17 cells assessed as increase in GalphaS-mediated CREB activation measured after 6 to 24 hrs by SEAP reporter gene-based chemiluminescence assay
|
Homo sapiens
|
0.02
nM
|
|
Journal : J Med Chem
Title : Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE<sub>1</sub> Series EP<sub>4</sub> Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE<sub>1</sub> Analog (KMN-159) as a Potent EP<sub>4</sub> Agonist.
Year : 2019
Volume : 62
Issue : 9
First Page : 4731
Last Page : 4741
Authors : Barrett SD, Holt MC, Kramer JB, Germain B, Ho CS, Ciske FL, Kornilov A, Colombo JM, Uzieblo A, O'Malley JP, Owen TA, Stein AJ, Morano MI.
Abstract : A series of small-molecule full agonists of the prostaglandin E<sub>2</sub> type 4 (EP<sub>4</sub>) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.
|
Agonist activity at human EP2 receptor expressed in HEK293T/17 cells assessed as increase in GalphaS-mediated CREB activation measured after 6 to 24 hrs by SEAP reporter gene-based chemiluminescence assay
|
Homo sapiens
|
9.3
nM
|
|
Journal : J Med Chem
Title : Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE<sub>1</sub> Series EP<sub>4</sub> Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE<sub>1</sub> Analog (KMN-159) as a Potent EP<sub>4</sub> Agonist.
Year : 2019
Volume : 62
Issue : 9
First Page : 4731
Last Page : 4741
Authors : Barrett SD, Holt MC, Kramer JB, Germain B, Ho CS, Ciske FL, Kornilov A, Colombo JM, Uzieblo A, O'Malley JP, Owen TA, Stein AJ, Morano MI.
Abstract : A series of small-molecule full agonists of the prostaglandin E<sub>2</sub> type 4 (EP<sub>4</sub>) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
8.59
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
1.048
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.08
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.08
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
