Demonstration of the innate electrophilicity of 4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6trifluoromethyl)pyrimidine (BETP), a small molecule positive allosteric modulator of the glucagon-like peptide-1. Drug Metab. Dispos

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

Convergent Syntheses of Isomeric Imidazolospiroketones as Templates for Acetyl-CoA Carboxylase (ACC) Inhibitors

The synthesis of imidazole fused spirocyclic ketones as templates for acetyl-CoA carboxylase (ACC) inhibitors is reported. By completing the spirocyclic ring closure via divergent pathways, the synthesis of these regioisomers from common intermediates was developed. Through an aldehyde homologation/transmetalation strategy, one isomer was formed selectively. The second desired isomer was obtained via an intramolecular aromatic homolytic substitution reaction. Preparation of these isomeric spiroketones provided templates which, upon elaboration, led to key structure–activity relationship (SAR) points for delivery of potent ACC inhibitors

Macrocyclizations for Medicinal Chemistry: Synthesis of Druglike Macrocycles by High-Concentration Ullmann Coupling

Conditions have been identified for the efficient Ullmann macrocyclization of phenol and imidazole nucleophiles with aryl iodides at high reaction concentrations of up to 100 mM and using 5–10 mol % loading of an inexpensive copper catalyst. A range of substitution patterns and ring sizes are tolerated, and the method has been exemplified by the synthesis of a set of druglike macrocycles