Continued optimization of the M5 NAM ML375: Discovery of VU6008667, an M5 NAM with high CNS penetration and a desired short half-life in rat for addiction studies

  • Bioorg Med Chem Lett. 2017 Mar 15;27(6):1356-1359. doi: 10.1016/j.bmcl.2017.02.020.
Kevin M McGowan  1 ,  Kellie D Nance  2 ,  Hykeyung P Cho  1 ,  Thomas M Bridges  1 ,  P Jeffrey Conn  1 ,  Carrie K Jones  1 ,  Craig W Lindsley  3
Affiliations
  • 1. 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.
  • 2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 3. 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: [email protected].
PMID: 28237763 DOI: 10.1016/j.bmcl.2017.02.020
Abstract

This letter describes the continued optimization of M5 NAM 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 M5 NAM of comparable potency to ML375, but with a rat t1/2 of 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 M5 NAM, with high CNS penetration, excellent selectivity versus M1-4 and the desired short half-life (t1/2=2.3h) in rat.

Keywords
CNS penetration; M(5); Muscarinic acetylcholine receptor; Pharmacokinetics; Structure-Activity Relationship (SAR).
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