Design and Synthesis of Prolylcarboxypeptidase (PrCP) Inhibitors To Validate PrCP As A Potential Target for Obesity

[摘要]：Prolycarboxypeptidase (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 1050 values of 1 and 2 nM and is not active (IC50 > 25 mu M) 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 reduction in PrCP KO mice.

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