VU6007477, a Novel M₁ PAM Based on a Pyrrolo[2,3-b]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events

Herein, we report the chemical optimization of a new series of M₁ positive allosteric modulators (PAMs) based on a novel pyrrolo[2,3-b]pyridine core, developed via scaffold hopping and iterative parallel synthesis. The vast majority of analogs in this series proved to display robust cholinergic seizure activity. However, by removal of the secondary hydroxyl group, VU6007477 resulted with good rat M₁ PAM potency (EC₅₀ = 230 nM, 93% ACh max), minimal M₁ agonist activity (agonist EC₅₀ > 10 μM), good CNS penetration (rat brain/plasma K _p = 0.28, K _p,uu = 0.32; mouse K _p = 0.16, K _p,uu = 0.18), and no cholinergic adverse events (AEs, e.g., seizures). This work demonstrates that within a chemical series prone to robust M₁ ago-PAM activity, SAR can result, which affords pure M₁ PAMs, devoid of cholinergic toxicity/seizure liability.