Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists

Thomas S Reger; Jasmine Zunic; Nicholas Stock; Bowei Wang; Nicholas D Smith; Benito Munoz; Mitchell D Green; Michael F Gardner; Joyce P James; Weichao Chen; Kenneth Alves; Qian Si; Kelly M Treonze; Russell B Lingham; Richard A Mumford

doi:10.1016/j.bmcl.2009.12.009

Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1173-6. doi: 10.1016/j.bmcl.2009.12.009. Epub 2009 Dec 4.

Authors

Thomas S Reger¹, Jasmine Zunic, Nicholas Stock, Bowei Wang, Nicholas D Smith, Benito Munoz, Mitchell D Green, Michael F Gardner, Joyce P James, Weichao Chen, Kenneth Alves, Qian Si, Kelly M Treonze, Russell B Lingham, Richard A Mumford

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, San Diego, CA 92121, USA. thomas_reger@merck.com

PMID: 20022493
DOI: 10.1016/j.bmcl.2009.12.009

Abstract

A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics.

Publication types

Comparative Study

MeSH terms

Animals
Binding, Competitive / physiology
Dipeptides / chemistry*
Dipeptides / metabolism*
Dipeptides / pharmacology
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / metabolism
Heterocyclic Compounds / pharmacology
Humans
Integrin alpha4beta1 / antagonists & inhibitors*
Integrin alpha4beta1 / metabolism
Proline / chemistry*
Proline / metabolism*
Proline / pharmacology
Protein Binding / physiology
Rats

Substances

Dipeptides
Heterocyclic Compounds
Integrin alpha4beta1
Proline