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

This letter describes the continued optimization of M NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375has an excessively long elimination half-life in rat (t=80h), which can be problematic in certain rodent addiction paradigms (e.g., reinstatement). Thus, we required an M NAM of comparable potency to ML375, but with a rat t 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 M NAM, with high CNS penetration, excellent selectivity versus M and the desired short half-life (t=2.3h) in rat.