Discovery of 3-aminopiperidines as potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitors

Jason M Cox; Bart Harper; Anthony Mastracchio; Barbara Leiting; Ranabir Sinha Roy; Reshma A Patel; Joseph K Wu; Kathryn A Lyons; Huaibing He; Shiyao Xu; Bing Zhu; Nancy A Thornberry; Ann E Weber; Scott D Edmondson

doi:10.1016/j.bmcl.2007.05.087

Discovery of 3-aminopiperidines as potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitors

Bioorg Med Chem Lett. 2007 Aug 15;17(16):4579-83. doi: 10.1016/j.bmcl.2007.05.087. Epub 2007 Jun 2.

Authors

Jason M Cox¹, Bart Harper, Anthony Mastracchio, Barbara Leiting, Ranabir Sinha Roy, Reshma A Patel, Joseph K Wu, Kathryn A Lyons, Huaibing He, Shiyao Xu, Bing Zhu, Nancy A Thornberry, Ann E Weber, Scott D Edmondson

Affiliation

¹ Merck Research Laboratories, Department of Medicinal Chemistry, PO Box 2000, Rahway, NJ 07065, USA. jason_cox@merck.com

PMID: 17562364
DOI: 10.1016/j.bmcl.2007.05.087

Abstract

Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles.

MeSH terms

Animals
Area Under Curve
Biological Availability
Dipeptidyl-Peptidase IV Inhibitors*
Half-Life
Humans
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology
Molecular Structure
Piperidines / blood
Piperidines / chemistry*
Piperidines / pharmacology*
Rats
Structure-Activity Relationship

Substances

Dipeptidyl-Peptidase IV Inhibitors
Hypoglycemic Agents
Piperidines