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-dihy-dro-5H-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. (C) 2016 Elsevier Ltd. All rights reserved.