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: Changyou Zhou, Margareta Garcia-Calvo, Shirly Pinto, Matthew Lombardo, Zhe Feng, Kate Bender, Kellyann D Pryor, Urmi R Bhatt, Renee M Chabin, Wayne M Geissler, Zhu Shen, Xinchun Tong, Zhoupeng Zhang, Kenny K Wong, Ranabir Sinha Roy, Kevin T Chapman, Lihu Yang, Yusheng Xiong
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 19 Pg. 7251-63 (Oct 14 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20857914 (Publication Type: Journal Article)

Chemical References

• 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
• Anti-Obesity Agents
• Benzimidazoles
• Blood Proteins
• Serine Proteinase Inhibitors
• Phenylalanine
• Carboxypeptidases
• lysosomal Pro-X carboxypeptidase

Topics

• Animals
• Anti-Obesity Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Benzimidazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Biological Availability
• Blood Proteins (metabolism)
• Carboxypeptidases (antagonists & inhibitors, genetics)
• Drug Design
• Humans
• Male
• Mice
• Mice, Knockout
• Obesity (drug therapy, enzymology)
• Phenylalanine (analogs & derivatives, chemical synthesis, pharmacokinetics, pharmacology)
• Protein Binding
• Serine Proteinase Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship