Discovery of Naphthyl-Fused 5‑Membered Lactams as a New Class of M₁ Positive Allosteric Modulators

Selective activation of the M₁ muscarinic receptor via positive allosteric modulation represents an original approach to treat the cognitive decline in patients with Alzheimer’s disease. A series of naphthyl-fused 5-membered lactams were identified as a new class of M₁ positive allosteric modulators and were found to possess good potency and in vivo efficacy

Identification of Amides as Carboxylic Acid Surrogates for Quinolizidinone-Based M₁ Positive Allosteric Modulators

Selective activation of the M₁ muscarinic receptor via positive allosteric modulation represents an approach to treat the cognitive decline in patients with Alzheimer's disease. A series of amides were examined as a replacement for the carboxylic acid moiety in a class of quinolizidinone carboxylic acid M₁ muscarinic receptor positive allosteric modulators, and leading pyran <b>4o</b> and cyclohexane <b>5c</b> were found to possess good potency and in vivo efficacy

MK-7622: A First-in-Class M₁ Positive Allosteric Modulator Development Candidate

Identification of ligands that selectively activate the M₁ muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M₁ muscarinic receptor that has entered Phase II studies in patients with Alzheimer’s disease