Fluorine and Deuterium to Improve Oral Bioavailability

In a recent article, Dr Angela D. Kerekes et al. described the PK optimization of a potent Aurora inhibitor 1. This compound presents a good PK profile for intravenous delivery but poor oral bioavailability in rats due to rapid metabolism and poor oral absorption. Metabolism studies determine that the compound undergoes N-desethyl and oxidation to generate metabolites 2 and 3.

To improve the PK, the initial strategy was to block N-Alkylation by introduction of fluorine (see compound 4). This modification improved the oral PK in rat but oral PK in monkey was unchanged. In further metabolism studies the failure of the fluorine addition to improve oral PK was attributed to an additional hydroxylation of the arylic position. The introduction of deuterium to that position resulted in a improved oral PK in monkey (see compound 5). This example demontrates that introduction of fluorine and deuterium when possible can be an excellent strategy to improve oral PK.

Angela D. Kerekes et al. J. Med. Chem. 2011 asap