title: Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380).
abstract: A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5 potency to arrive at the most potent M5 PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5 EC50 = 190 nM, rat M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).
authors.affiliation: Department of Pharmacology, ‡Vanderbilt Center for Neuroscience Drug Discovery, and §Vanderbilt Specialized Chemistry Center for Accelerated Probe Development (MLPCN), Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Gentry
authors.forename: Masaya
authors.initials: M
authors.lastname: Kokubo
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Noetzel
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Atin
authors.initials: A
authors.lastname: Lamsal
authors.forename: Emery
authors.initials: E
authors.lastname: Smith
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hodder
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043642:Receptor, Muscarinic M5 / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C000593260:1-((1H-Indazol-5-yl)sulfonyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide; D007191:Indazoles; D010880:Piperidines; D043642:Receptor, Muscarinic M5; D013449:Sulfonamides; C032727:piperidine