title: Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold.
abstract: One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M(1) muscarinic receptor. A number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M(2) to M(5) subtypes. One strategy to confer selectivity for M(1) is the identification of positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M(1) positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, United States. scott_d_kuduk@merck.com
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Chang
authors.forename: Christina N
authors.initials: CN
authors.lastname: Di Marco
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Pitts
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Greshock
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.forename: Marion
authors.initials: M
authors.lastname: Wittmann
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Seager
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Koeplinger
authors.forename: Charles D
authors.initials: CD
authors.lastname: Thompson
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
authors.forename: William J
authors.initials: WJ
authors.lastname: Ray
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D018678:Cholinergic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D005239:Fear / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054837:Quinolizidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011807:Quinolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043643:Receptor, Muscarinic M1 / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: C561237:1-((4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; D018678:Cholinergic Agents; D009570:Nitriles; D018697:Nootropic Agents; D010880:Piperidines; D054837:Quinolizidines; D011807:Quinolizines; D043643:Receptor, Muscarinic M1