title: Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity.
abstract: 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 (IC(50) > 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories,Rahway, New Jersey 07065, USA.
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhou
authors.forename: Margareta
authors.initials: M
authors.lastname: Garcia-Calvo
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
authors.forename: Matthew
authors.initials: M
authors.lastname: Lombardo
authors.forename: Zhe
authors.initials: Z
authors.lastname: Feng
authors.forename: Kate
authors.initials: K
authors.lastname: Bender
authors.forename: Kellyann D
authors.initials: KD
authors.lastname: Pryor
authors.forename: Urmi R
authors.initials: UR
authors.lastname: Bhatt
authors.forename: Renee M
authors.initials: RM
authors.lastname: Chabin
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Geissler
authors.forename: Zhu
authors.initials: Z
authors.lastname: Shen
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Zhoupeng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Kenny K
authors.initials: KK
authors.lastname: Wong
authors.forename: Ranabir Sinha
authors.initials: RS
authors.lastname: Roy
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Chapman
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C553300:2-amino-N-(3-(biphenyl-4-yl)-1-(2-(5,6-dichloro-1H-benzimidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-yl)-2-methylpropanamide; D019440:Anti-Obesity Agents; D001562:Benzimidazoles; D001798:Blood Proteins; D015842:Serine Proteinase Inhibitors; D010649:Phenylalanine; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase