Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation

Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound <b>15</b> (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log <i>D</i>, improving solubility, and minimizing chemical lability. Compound <b>15</b> achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge

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