Biotransformation of Navoximod
Some super interesting biotransformations were published by Shuai Wang and colleagues at Genentech in DMD this month. If your compounds contain imidazoles check out what happened to this trifused ring system in navoximod. Epoxidation, hydrolysis and ring opening resulted in release of cyanide which led to an unexpected long circulating thiocyanate metabolite through the action of a mitochondrial thiosulfate sulfurtransferase. This was a major metabolite in rat (30% in circulation) but much less so in dog (5.5%) and human (4.4%). Also of interest is the chiral inversion metabolite M51, another major metabolite in rat.
In dog and humans, glucuronidation dominated, however the major O-glucuronide was different between species. Also to note, M28 was only observed in hepatocytes, whereas only M19 was observed in UDPGA supplemented Liver microsomes.
Paper
Cyanide Release and Glucuronidation for Navoximod
Shuai Wang, Shuguang Ma, Eugene Chen, Jing Wang, Hoa Le, Steven Paul Hanlon, Martin Binder, Wendy Lee, S. Cyrus Khojasteh and Laurent Salphati
Drug Metabolism and Disposition July 1, 2023, 51 (7) 862-872; DOI: https://doi.org/10.1124/dmd.123.001289
