Design, synthesis and SAR of a series of 1,3,5-trisubstituted benzenes as thrombin inhibitors

Richard C A Isaacs; Christina L Newton; Kellie J Cutrona; Swati P Mercer; Linda S Payne; Kenneth J Stauffer; Peter D Williams; Jacquelynn J Cook; Julie A Krueger; S Dale Lewis; Bobby J Lucas; Elizabeth A Lyle; Joseph J Lynch; Daniel R McMasters; Adel M Naylor-Olsen; Maria T Michener; Audrey A Wallace

doi:10.1016/j.bmcl.2010.12.105

Design, synthesis and SAR of a series of 1,3,5-trisubstituted benzenes as thrombin inhibitors

Bioorg Med Chem Lett. 2011 Mar 1;21(5):1536-40. doi: 10.1016/j.bmcl.2010.12.105. Epub 2010 Dec 28.

Authors

Richard C A Isaacs¹, Christina L Newton, Kellie J Cutrona, Swati P Mercer, Linda S Payne, Kenneth J Stauffer, Peter D Williams, Jacquelynn J Cook, Julie A Krueger, S Dale Lewis, Bobby J Lucas, Elizabeth A Lyle, Joseph J Lynch, Daniel R McMasters, Adel M Naylor-Olsen, Maria T Michener, Audrey A Wallace

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. richard_isaacs@verizon.net

PMID: 21295467
DOI: 10.1016/j.bmcl.2010.12.105

Abstract

A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5-trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency.

MeSH terms

Antithrombins / chemical synthesis*
Antithrombins / chemistry
Antithrombins / pharmacology
Benzene / chemical synthesis*
Benzene / chemistry
Benzene / pharmacology
Drug Design*
Humans
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Thrombin / antagonists & inhibitors*

Substances

Antithrombins
Thrombin
Benzene