Synthesis of Deuterated Heterocycles with Me2NCD(OMe)2 and Evaluation of the Products for Metabolism by Aldehyde Oxidase.

The metabolic oxidation of drug-like small molecules by aldehyde oxidase (AO) has commonly been mitigated through the incorporation of deuterium at the oxidation site. We report that dimethylformamide dimethyl acetal and related compounds undergo rapid CH to CD isotopic exchange upon exposure to methanol-d and similar deuterated alcohols. This isotopic exchange process can be used to synthesize Me2NCD(OMe)2 and has significant implications for the use of Me2NCD(OMe)2 in the synthesis of specifically deuterium-labeled compounds. The application of Me2NCD(OMe)2 to the synthesis of various heterocycles that have been associated with AO metabolism is described, and we report the impact of deuteration on the rate of in vitro AO-mediated metabolism.

Discovery of novel quinolinone adenosine A2B antagonists.

A novel series of quinolinone-based adenosine A(2B) receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A(2B) antagonist (2i) which exhibited potent activity in a cAMP accumulation assay (5.1 nM) and an IL-8 release assay (0.4 nM).