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Design and Synthesis of γ- and δ-Lactam M 1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M 1-Selective PAM with Weak Agonist Activity

Design and Synthesis of γ- and δ-Lactam M 1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M 1-Selective PAM with Weak Agonist Activity

Jennifer E Davoren, Michelle Garnsey, Betty Pettersen, Michael A Brodney, Jeremy R Edgerton, Jean-Philippe Fortin, Sarah Grimwood, Anthony R Harris, Stephen Jenkinson, Terry Kenakin, John T Lazzaro, Che-Wah Lee, etc.

J Med Chem. 2017 Aug 10;60(15):6649-6663.

PMID: 28598634

Abstract:

Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M1 is sufficient to elicit cholinergic AEs.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4244757	PF-06827443			Price

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