Discovery of Bis-Acyl Hydrazides as Potent and Bioavailable MTA-Cooperative PRMT5 Inhibitors: A Case Study of Leveraging the Deuterium Kinetic Isotope Effect

We describe the discovery of a series of potent, selective,
and
orally bioavailable bis-acyl hydrazide inhibitors targeting the PRMT5·MTA
complex for the treatment of MTAP-deleted cancers. Key to this discovery
was the identification of major metabolite M1, resulting
from N-demethylation of lead inhibitor compound 12, as a potent hERG inhibitor. Leveraging the kinetic isotope
effect, we generated methyl-d3 analog 16 which reduced the formation of M1 in vivo,
resulting in acceptable safety margins and an improved pharmacokinetic
profile. Our data suggest this strategy could be employed more broadly
to reduce undesirable metabolism of methylated amines.