Abstract
This letter describes the continued optimization of M(5) NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375has an excessively long elimination half-life in rat (t(1/2)=80h), 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 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(5) NAM, with high CNS penetration, excellent selectivity versus M(1-4) and the desired short half-life (t(1/2)=2.3h) in rat.