2' biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling.
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.
Budzik
Brian
B
Discovery Research and Centers of Excellence for Drug Discovery, GlaxoSmithKline, Collegeville, PA 19426, USA. torqux@yahoo.com
Garzya
Vincenzo
V
Shi
Dongchuan
D
Walker
Graham
G
Lauchart
Yann
Y
Lucas
Adam J
AJ
Rivero
Ralph A
RA
Langmead
Christopher J
CJ
Watson
Jeannette
J
Wu
Zining
Z
Forbes
Ian T
IT
Jin
Jian
J
D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D055808:Drug Discovery; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D000577:Amides; D006841:Hydrocarbons, Aromatic; D043643:Receptor, Muscarinic M1