Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration.

This Letter describes the continued chemical optimization of the VU0453595 series of M 1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5 H -pyrrolo[3,4- b ]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M 1 PAM potency, but significantly improved CNS distribution ( K p s 0.3–3.1). Moreover, this campaign provided fundamentally distinct M 1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors. [ABSTRACT FROM AUTHOR]