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. Epub 2017 Feb 13.

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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Central Nervous System / metabolism*
  • Half-Life
  • Muscarinic Antagonists / pharmacokinetics
  • Muscarinic Antagonists / pharmacology*
  • Rats
  • Receptor, Muscarinic M5 / drug effects*

Substances

  • Muscarinic Antagonists
  • Receptor, Muscarinic M5