Design and Synthesis of γ- and δ‑Lactam M₁ Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M₁‑Selective PAM with Weak Agonist Activity

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 <b>1</b> (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M₁-selective PAM with minimal agonist activity. Compound <b>1</b> 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

Design and Synthesis of γ- and δ‑Lactam M₁ Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M₁‑Selective PAM with Weak Agonist Activity

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 <b>1</b> (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M₁-selective PAM with minimal agonist activity. Compound <b>1</b> 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

Discovery of the Potent and Selective M1 PAM-Agonist <i>N</i>‑[(3<i>R</i>,4<i>S</i>)‑3-Hydroxytetrahydro‑2<i>H</i>‑pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]­pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects

It is hypothesized that selective muscarinic M₁ subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer’s disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M₁ with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M₁ activation. This manuscript describes the development of a series of M₁-selective pyridone and pyridine amides and their key pharmacophores. Compound <b>38</b> (PF-06767832) is a high quality M₁ selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M₂/M₃ subtype activity, compound <b>38</b> still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M₁ activation contributes to the cholinergic liabilities that were previously attributed to activation of the M₂ and M₃ receptors