Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core.

Abstract This Letter describes the chemical optimization of a novel series of M 4 positive allosteric modulators(PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3- d ]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma K p = 0.74), within the original core after several rounds of optimization; however, the thieno[2,3- d ]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M 4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma K p > 10). Moreover, this campaign provided fundamentally distinct M 4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.