Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases.
Berotralstat is an oral plasma kallikrein inhibitor BCX7353 for treatment of hereditary angioedema.
[1] GRAS J. Berotralstat. Plasma kallikrein (KLKB1) inhibitor, Treatment of hereditary angioedema attacks[J]. Drugs of The Future, 2021, 54 1: 21. DOI:10.1358/DOF.2021.46.1.3220730.
Berotralstat (BCX-7353) can be prepared by Grignard reaction of magnesium [3-[bis(trimethylsilyl) amino]-4-fluorophenyl](bromido)magnesium with 3-formylbenzonitrile in THF to give secondary alcohol , which is condensed with Boc-protected acid in the presence of PyBrop and DIEA in DMF to yield the corre sponding amide. Chlorination of alcohol with SOCl2 in CH2Cl2, followed by condensation with cyclopropylmethan amine in acetonitrile at 70 °C affords secondary amine, which is N-deprotected with HCl in dioxane to yield racemic berotralstat. Resolution of racemate by preparative SFC gives (R)-berotralstat.
