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

Discovery and Characterization of (<i>R</i>)‑6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1‑<i>c</i>][1,4]oxazin-4(9<i>H</i>)‑one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates

We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu₅ negative allosteric modulator (NAM) <b>7</b>. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu₅ NAMs. Increasing the sp³ character of high-throughput screening hit <b>40</b> afforded a novel morpholinopyrimidone mGlu₅ NAM series. Its prototype, (<i>R</i>)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido­[2,1-<i>c</i>]­[1,4]­oxazin-4­(9<i>H</i>)-one (PF-06462894, <b>8</b>), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound <b>8</b> did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that <b>8</b> did not form any reactive metabolites. However, <b>8</b> caused the identical microscopic skin lesions in NHPs found with <b>7</b>, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance

Discovery and Preclinical Characterization of 1‑Methyl‑3-(4‑methylpyridin‑3‑yl)‑6‑(pyridin‑2‑ylmethoxy)‑1<i>H</i>‑pyrazolo-[3,4‑<i>b</i>]­pyrazine (PF470): A Highly Potent, Selective, and Efficacious Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator

A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (<b>1</b>), a systematic structure–activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1<i>H</i>-pyrazolo­[3,4-<i>b</i>]­pyrazine (PF470, <b>14</b>) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound <b>14</b> demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of <b>14</b> to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study

Discovery and Characterization of (<i>R</i>)‑6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1‑<i>c</i>][1,4]oxazin-4(9<i>H</i>)‑one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates

We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu₅ negative allosteric modulator (NAM) <b>7</b>. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu₅ NAMs. Increasing the sp³ character of high-throughput screening hit <b>40</b> afforded a novel morpholinopyrimidone mGlu₅ NAM series. Its prototype, (<i>R</i>)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido­[2,1-<i>c</i>]­[1,4]­oxazin-4­(9<i>H</i>)-one (PF-06462894, <b>8</b>), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound <b>8</b> did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that <b>8</b> did not form any reactive metabolites. However, <b>8</b> caused the identical microscopic skin lesions in NHPs found with <b>7</b>, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance