Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema

Hereditary angioedema
(HAE) is a rare genetic disorder in which
patients experience sudden onset of swelling in various locations
of the body. HAE is associated with uncontrolled plasma kallikrein
(PKa) enzyme activity and generation of the potent inflammatory mediator,
bradykinin, resulting in episodic attacks of angioedema. Herein, we
disclose the discovery and optimization of novel small molecule PKa
inhibitors. Starting from molecules containing highly basic P1 groups,
which typically bind to an aspartic acid residue (Asp189) in the serine
protease S1 pocket, we identified novel P1 binding groups likely to
have greater potential for oral-drug-like properties. The optimization
of P4 and the central core together with the particularly favorable
properties of 3-fluoro-4-methoxypyridine P1 led to the development
of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor
in phase 3 for on-demand treatment of HAE attacks.