Document Report Card

ID: ALA1255224

Journal: J Med Chem

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

Authors: 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.

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.

CiteXplore: 20857914

DOI: 10.1021/jm101013m