De Novo Design in an M₁ Positive Allosteric Modulator Backup Program: The Discovery of VU6069863

Recently, we disclosed our M₁ PAM that had advanced into Phase I clinical studies, VU0467319, as well as a deuterated back-up compound, VU6045422, to address a major metabolite produced in man and improve tox profile. Ultimately, this series failed to overcome its liabilities and was terminated. However, the team was challenged with developing chemically distinct backup candidates without performing a new HTS campaign. De novo design strategies based upon the other two M₁ ago-PAMs that had previously entered clinical development, MK-7622 and TAK-071, led to the discovery of a fundamentally new chemotype based on a 3,4-dihydrobenzo-[f]-[1,4]-oxazepin-5-(2H)-one core, providing VU6069863. VU6069863 proved to be an M₁ PAM (EC₅₀ = 248 nM, 87% ACh Max) with minimal M₁ agonism, (EC₅₀ > 30 μM, 19% ACh Max) despite being derived from potent M₁ ago-PAM chemotypes, with good CNS penetration (rat K_p = 0.59, K_p,uu = 0.13, MDCK-MDR1 ER = 1.8, P_app = 32.8 × 10^-6 cm/s) and pro-cognitive efficacy in both contextual fear conditioning (minimally effective dose [MED] = 0.1 mg/kg PO) and novel object recognition (MED = 1 mg/kg PO) in rats.