Demonstration of the Innate Electrophilicity of 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor
作者： Heather Eng , Raman Sharma , Thomas S. McDonald , David J. Edmonds , Jean-Philippe Fortin
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摘要: 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagon-like peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore quantitative pharmacology associated with GLP-1R agonism preclinical species, vivo pharmacokinetics BETP were examined after oral dosing. Failure to detect circulation administration 10-mg/kg dose was consistent lack an insulinotropic effect orally administered this species. Likewise, systemic concentrations rat upon (1 mg/kg) minimal (and sporadic). In vitro incubations bovine serum albumin, plasma, liver microsomes from rodents humans indicated facile degradation BETP. metabolites plasma microsomal absence NADP suggestive covalent interaction between protein amino acid residue(s) these matrices. Incubations glutathione (GSH) buffer revealed rapid nucleophilic displacement ethylsulfoxide functionality by GSH yield adduct M1, which that intrinsically electrophilic. The structure M1 unambiguously identified comparison its chromatographic mass spectral properties authentic standard. conjugate also characterized NADPH- GSH-supplemented samples pharmacokinetic studies. Unlike BETP, inactive as allosteric modulator GLP-1R.
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