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

This letter describes the continued optimization of M-5 NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375 has an excessively long elimination half-life in rat (t(1/2) = 80 h), which can be problematic in certain rodent addiction paradigms (e.g., reinstatement). Thus, we required an M-5 NAM of comparable potency to ML375, but with a rat t(1/2) of less than 4 h. 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-5 NAM, with high CNS penetration, excellent selectivity versus M1-4 and the desired short half-life (t(1/2) = 2.3 h) in rat. (C)2017 Elsevier Ltd. All rights reserved.