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.

Autor:	Gelin CF; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Stenne B; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Coate H; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Hiscox A; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Soyode-Johnson A; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Wall JL; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Lord B; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Schoellerman J; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Coe KJ; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Wang K; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Alcázar J; Janssen Research & Development, Janssen-Cilag, S.A., Jarama 75A, 45007 Toledo, Spain., Chrovian CC; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Dvorak CA; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Carruthers NI; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Koudriakova T; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Balana B; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States., Letavic MA; Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Feb 23; Vol. 66 (4), pp. 2877-2892. Date of Electronic Publication: 2023 Feb 09.
DOI:	10.1021/acs.jmedchem.2c01916
Abstrakt:	Herein, we describe a series of substituted 1 H -((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 1 H -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 ED 50 of 1.7 mg/kg.
Databáze:	MEDLINE
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