Distal kinetic deuterium isotope effect: Phenyl ring deuteration attenuates N-demethylation of Lu AF35700

The N-demethylation of zicronapine (7) and three of its deuterated analogs 8 – 10 has been studied in human in vitro metabolism systems. While the N-deuterio-methyl analog 8 did not behave differently from the parent in human liver microsomes, a significantly reduced rate of N-demethylation was observed as a consequence of benzene ring deuteration (compound 7 vs. 9). Additional deuteration of the N-methyl group, which as mentioned had shown no effect in isolation, further decreased the rate of the N-demethylation reaction (compound 10 vs. 9). This paper presents and discusses this unprecedented ‘distal kinetic isotope effect’ that was observed when incubating the test compounds with human liver microsomes or recombinant human CYP450 liver enzymes.