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Discovery of a Series of Substituted 1 H -((1,2,3-Triazol-4-yl)methoxy)pyrimidines as Brain Penetrants and Potent GluN2B-Selective Negative Allosteric Modulators

2023; American Chemical Society; Volume: 66; Issue: 4 Linguagem: Inglês

10.1021/acs.jmedchem.2c01916

1520-4804

Christine F. Gelin, Brice Stenne, Heather Coate, Afton Hiscox, Akinola Soyode-Johnson, Jessica L. Wall, Brian Lord, Jeffrey Schoellerman, Kevin J. Coe, Kai Wang, Jesús Alcázar, Christa C. Chrovian, Curt A. Dvorak, Nicholas I. Carruthers, Tatiana Koudriakova, Bartosz Balana, Michael A. Letavic,

Pharmacological Receptor Mechanisms and Effects

Herein, we describe a series of substituted 1H-((1,2,3-triazol-4-yl)methoxy)pyrimidines as potent GluN2B negative allosteric modulators. Exploration of several five- and six-membered heterocycles led to the identification of O-linked pyrimidine analogues that possessed a balance of potency and desirable ADME profiles. Due to initial observations of metabolic saturation, early metabolite identification studies were conducted on compound 18, and the results drove further iterative optimization efforts to avoid the formation of undesired saturating metabolites. The comprehensive investigation of substitution on the pyrimidine moiety of the 1H-1,2,3-triazol-4-yl)methoxy)pyrimidines allowed for the identification of compound 31, which demonstrated high GluN2B receptor affinity, improved solubility, and a clean cardiovascular profile. Compound 31 was profiled in an ex vivo target engagement study in rats at a 10 mg/kg oral dose and achieved an ED50 of 1.7 mg/kg.