Synthesis and pharmacokinetic profile of highly deuterated brecanavir analogs

Several highly deuterated analogs of the HIV-1 protease inhibitor brecanavir have been prepared to study the effect of deuterium upon metabolic stability. The sites for deuterium incorporation were initially chosen to maximize the potential for a kinetic isotope effect; locations where C–H bond breaking is the rate limiting step. The analogs have been profiled in both in vitro and in vivo pharmacokinetic studies and the result will be described herein.

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► d16 and d19 analogs of the HIV protease inhibitor brecanavir were synthesized.
► Metabolic ID studies were used to identify possible metabolic soft spots.
► Rat in vivo studies demonstrated no benefit to deuterium incorporation.
► Several instances of metabolism occurring on deuterated sites suggest the KIE was not sufficient to overcome oxidation.