title: Continued optimization of the M5NAM ML375: Discovery of VU6008667, an M5NAM with high CNS penetration and a desired short half-life in rat for addiction studies.
abstract: This letter describes the continued optimization of M5NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375has an excessively long elimination half-life in rat (t1/2=80h), which can be problematic in certain rodent addiction paradigms (e.g., reinstatement). Thus, we required an M5NAM of comparable potency to ML375, but with a rat t1/2of less than 4h. Steep SAR plagued this chemotype, and here we detail aniline replacements that offered some improvements over ML375, but failed to advance. Ultimately, incorporation of a single methyl group to the 9b-phenyl ring acted as a metabolic shunt, providing (S)-11 (VU6008667), an equipotent M5NAM, with high CNS penetration, excellent selectivity versus M1-4and the desired short half-life (t1/2=2.3h) in rat.
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: McGowan
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Kellie D
authors.initials: KD
authors.lastname: Nance
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Hykeyung P
authors.initials: HP
authors.lastname: Cho
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology and Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D006207:Half-Life; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043642:Receptor, Muscarinic M5 / Q000187:drug effects*
chemical_list: D018727:Muscarinic Antagonists; D043642:Receptor, Muscarinic M5
keywords: CNS penetration; M(5); Muscarinic acetylcholine receptor; Pharmacokinetics; Structure-Activity Relationship (SAR)