Multikilogram Synthesis of a Hepatoselective Glucokinase Activator

This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone α-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively non-nucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator

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 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