M3 muscarinic acetylcholine receptor antagonists: SAR and optimization of bi-aryl amines

Brian Budzik; Yonghui Wang; Dongchuan Shi; Feng Wang; Haibo Xie; Zehong Wan; Chongye Zhu; James J Foley; Parvathi Nuthulaganti; Lorena A Kallal; Henry M Sarau; Dwight M Morrow; Michael L Moore; Ralph A Rivero; Michael Palovich; Michael Salmon; Kristen E Belmonte; Dramane I Laine; Jian Jin

doi:10.1016/j.bmcl.2009.01.098

M3 muscarinic acetylcholine receptor antagonists: SAR and optimization of bi-aryl amines

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1686-90. doi: 10.1016/j.bmcl.2009.01.098. Epub 2009 Feb 4.

Affiliation

¹ Centers of Excellence for Drug Discovery, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.

PMID: 19243945
DOI: 10.1016/j.bmcl.2009.01.098

Abstract

Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M(3) muscarinic acetylcholine receptor antagonists such as 14 (pA(2)=11.0) possessing good sub-type selectivity for M(3) over M(2). The structure-activity relationships (SAR) and optimization of the bi-aryl amine series are described.

MeSH terms

Amides / chemistry
Amines / chemical synthesis*
Amines / pharmacology
Asthma / drug therapy
Chemistry, Pharmaceutical / methods*
Drug Design
Electrons
Humans
Inhibitory Concentration 50
Kinetics
Models, Chemical
Molecular Structure
Pulmonary Disease, Chronic Obstructive / drug therapy
Receptor, Muscarinic M3 / antagonists & inhibitors*
Receptor, Muscarinic M3 / chemistry
Structure-Activity Relationship

Substances

Amides
Amines
Receptor, Muscarinic M3