US EPA

7457981 

Journal Article 

Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity 

Zhou, C; Garcia-Calvo, M; Pinto, S; Lombardo, M; Feng, Z; Bender, K; Pryor, KD; Bhatt, UR; Chabin, RM; Geissler, WM; Shen, Z; Tong, X; Zhang, Z; Wong, KK; Roy, RS; Chapman, KT; Yang, L; Xiong, Y 

2010 

Yes 

Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 

American Chemical Society 

53 

19 

7251-7263 

English 

10.1021/jm101013m 

Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC 50 values of 1 and 2 nM and is not active (IC50 > 25 μM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP-/- and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice. © 2010 American Chemical Society. 

1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl] 3 (3 phenyl 1,2,4 oxadiazol 5 yl)propan 1 one; 2 amino 3 (biphenyl 4 yl) 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]propan 1 one; 3 (2' methylbiphenyl 4 yl) 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]propan 1 one; 3 (3' aminobiphenyl 4 yl) 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]propan 1 one; 3 (biphenyl 4 yl) 1 [2 (4 phenyl 1h imidazol 2 yl)pyrolidin 1 yl]propan 1 one; 3 [[(9h fluoren 9 ylmethoxy)carbonyl]amino] 4 oxo 4 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]butanoic acid; 4 [[(9h fluoren 9 ylmethoxy)carbonyl]amino] 5 oxo 5 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]pentanoic acid; 4' [2-[(tert butoxycarbonyl)amino] 3 oxo 3 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]propyl]biphenyl 4 carboxylic acid; 9h fluoren 9 ylmethyl [1 oxo 1 [(2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]butan 2 yl]carbamate; 9h fluoren 9 ylmethyl [1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]octan 2 yl]carbamate; 9h fluoren 9 ylmethyl [1 oxo 5 phenyl 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]pentan 2 yl]carbamate; 9h fluoren 9 ylmethyl [3 (benzyloxy) 1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]propan 2 yl]carbamate; 9h fluoren 9 ylmethyl[3 (biphenyl 4 yl) 1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]propan 2 yl]carbamate; 9h fluoren 9 ylmethyl[3 hydroxy 1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]propan 2 yl]carbamate; 9h fluoren 9 ylmethyl[4 (methylsulfanyl) 1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]butan 2 yl]carbamate; 9h fluoren 9 ylmethyl[4 (methylsulfonyl) 1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]butan 2 yl]carbamate; 9h fluoren 9 ylmethyl[5 amino 1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)]pentan 2 yl]carbamate; 9h fluoren 9 ylmethyl[6 amino 1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]hexan 2 yl]carbamate; 9h fluoren 9 ylmethyl[6 amino 1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1yl]hexan 2 yl]carbamate; benzyl [5 [[(9h fluoren 9 ylmethoxy)carbonyl]amino] 6 oxo 6 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]hexyl]carbamate; dipeptidyl carboxypeptidase inhibitor; n [3 (biphenyl 4 yl) 1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]propan 2 yl] 3,3 dimethylbutanamide; n[1 oxo 1 [2 (5 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]hexan 2 yl]acetamide; proline carboxypeptidase; proline carboxypeptidase inhibitor; prop 2 en 1 yl [5 [[(9h fluoren 9 ylmethoxy)carbonyl]amino] 6 oxo 6 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1yl]hexyl]carbamate; serine proteinase; tert butyl 7 [[(9h fluoren 9 ylmethoxy)carbonyl]amino]8 oxo 8 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]octanoate; tert butyl[3 (biphenyl 4 yl) 1 oxo 1 [2 (4 phenyl 1h imidazol 2 yl)pyrrolidin 1 yl]propan 2 yl]carbamate; unclassified drug; unindexed drug; 2-amino-N-(3-(biphenyl-4-yl)-1-(2-(5,6-dichloro-1H-benzimidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-yl)-2-methylpropanamide; antiobesity agent; benzimidazole derivative; carboxypeptidase; lysosomal Pro-X carboxypeptidase; phenylalanine; plasma protein; protein binding; serine proteinase inhibitor; animal experiment; animal model; area under the curve; article; asymmetric synthesis; chirality; controlled study; drug binding; drug bioavailability; drug clearance; drug design; drug potency; drug structure; drug synthesis; enzyme inhibition; IC 50; male; metabolic regulation; mouse; nonhuman; obesity; protein binding; weight reduction; analogs and derivatives; animal; antagonists and inhibitors; bioavailability; enzymology; genetics; human; knockout mouse; metabolism; obesity; stereoisomerism; structure activity relation; synthesis; Animals; Anti-Obesity Agents; Benzimidazoles; Biological Availability; Blood Proteins; Carboxypeptidases; Drug Design; Humans; Male; Mice; Mice, Knockout; Obesity; Phenylalanine; Protein Binding; Serine Proteinase Inhibitors; Stereoisomerism; Structure-Activity Relationship