molecules of the month

The Biocryst oral plasma kallikrein inhibitor, berotralstat (BCX7353), was recently approved as the first non-steroidal treatment for prevention of hereditary angioedema attacks. The molecule is given orally (150 mg QD) despite having two basic amines. Interestingly for a chronically administered drug, the molecule is noted to have QT prolongation risk at ~3x the recommended dose (450 mg), which appears acceptable for this rare and underserved indication. The molecule was discovered after a structure-based drug design campaign starting with knowledge from a previously poorly bioavailable benzamidine-containing zwitterion, avoralstat (BCX4161). The benzamidine was successfully replaced with a similarly basic benzylamine, and the new benzylamine-containing fragment was elaborated into molecule with a highly dissimilar structure and binding mode from the original drug. There…