title: SAR studies on carboxylic acid series M(1) selective positive allosteric modulators (PAMs).
abstract: There is mounting evidence from preclinical and early proof-of-concept studies suggesting that selective modulation of the M1 muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD). A number of nonselective M1 muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M2 to M5 sub-types. Thus, there is a need to identify selective activators of the M1 receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M1 is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M1 receptor rather than the highly conserved orthosteric acetylcholine binding site. BQCA has been identified as a highly selective carboxylic acid M1 PAM and this review focuses on an extensive lead optimization campaign undertaken on this compound.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. douglas_beshore@merck.com.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Beshore
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018721:Muscarinic Agonists / Q000737:chemistry* / Q000494:pharmacology; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D002264:Carboxylic Acids; D018721:Muscarinic Agonists; D015363:Quinolones; D043643:Receptor, Muscarinic M1; D054852:Small Molecule Libraries