mech.-based inh. of monoamine oxidase LSD1
orally efficacious in xenograft model
from optimization of known starting point
ACS Med. Chem. Lett., May 12, 2020
Constellation Pharma., Cambridge, MA
“Compound 34” is a mechanism-based inhibitor of lysine-specific demethylase LSD1 (aka KDM1A). LSD1 has an FAD co-factor which is covalently modified by the cyclopropylamine in compound 34 likely through an electron-transfer mechanism (as for tranylcypromine and MAOs). Interestingly, the 4,4-spiro amine provided an improvement to in vitro microsomal stability over the corresponding piperidine analog without a significant change in cLogD. The compound demonstrated activity in a xenograft model at doses as low as 0.5 mg/kg QD.