Discovery of a new class of potent prolylcarboxypeptidase inhibitors derived from alanine

Zhicai Wu; Cangming Yang; Yusheng Xiong; Zhe Feng; Matthew Lombardo; Andreas Verras; Renee M Chabin; Suoyu Xu; Xinchun Tong; Dan Xie; Mike E Lassman; Urmi R Bhatt; Margarita M Garcia-Calvo; Wayne Geissler; Zhu Shen; Qing Chen; Ranabir Sinharoy; Jeffrey J Hale; James R Tata; Shirly Pinto; Dong-Ming Shen; Steven L Colletti

doi:10.1016/j.bmcl.2011.12.064

Discovery of a new class of potent prolylcarboxypeptidase inhibitors derived from alanine

Bioorg Med Chem Lett. 2012 Feb 15;22(4):1774-8. doi: 10.1016/j.bmcl.2011.12.064. Epub 2011 Dec 24.

Affiliation

¹ Department of Discovery Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. zhicai_wu@merck.com

PMID: 22248857
DOI: 10.1016/j.bmcl.2011.12.064

Abstract

Efforts to modify the central proline portion of lead compound 4 lead to the discovery of novel prolylcarboxypeptidase (PrCP) inhibitors. Especially, replacement with alanine afforded compound 19 displaying more potent human and mouse PrCP inhibitory activity than 4 and an overall comparable profile.

MeSH terms

Alanine / chemistry*
Alanine / pharmacology
Animals
Carboxypeptidases / antagonists & inhibitors*
Drug Discovery*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Inhibitory Concentration 50
Mice
Molecular Structure
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Carboxypeptidases
lysosomal Pro-X carboxypeptidase
Alanine