2' biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling

Brian Budzik; Vincenzo Garzya; Dongchuan Shi; Graham Walker; Yann Lauchart; Adam J Lucas; Ralph A Rivero; Christopher J Langmead; Jeannette Watson; Zining Wu; Ian T Forbes; Jian Jin

doi:10.1016/j.bmcl.2010.04.127

2' biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling

Bioorg Med Chem Lett. 2010 Jun 15;20(12):3545-9. doi: 10.1016/j.bmcl.2010.04.127. Epub 2010 May 17.

Authors

Brian Budzik¹, Vincenzo Garzya, Dongchuan Shi, Graham Walker, Yann Lauchart, Adam J Lucas, Ralph A Rivero, Christopher J Langmead, Jeannette Watson, Zining Wu, Ian T Forbes, Jian Jin

Affiliation

¹ Discovery Research and Centers of Excellence for Drug Discovery, GlaxoSmithKline, Collegeville, PA 19426, USA. torqux@yahoo.com

PMID: 20483599
DOI: 10.1016/j.bmcl.2010.04.127

Abstract

Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.

MeSH terms

Amides / chemical synthesis*
Amides / pharmacokinetics*
Amides / pharmacology
Animals
Blood-Brain Barrier / metabolism
Central Nervous System / metabolism
Drug Discovery
Hydrocarbons, Aromatic / chemical synthesis*
Hydrocarbons, Aromatic / pharmacokinetics*
Hydrocarbons, Aromatic / pharmacology
Molecular Structure
Rats
Receptor, Muscarinic M1 / agonists*
Structure-Activity Relationship
Tissue Distribution

Substances

Amides
Hydrocarbons, Aromatic
Receptor, Muscarinic M1