Plasma kallikrein (PKa) is a trypsin-like serine protease that circulates in the plasma and is implicated in a number of inflammatory and edematous disorders including hereditary angioedema (HAE), a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. Uncontrolled PKa enzyme activity leads to amplification of the contact activation pathway through activation of both plasma prekallikrein to PKa and FXII to active Factor XIIa and ultimately liberation of the potent inflammatory mediator, bradykinin (BK), from its substrate, high molecular weight kininogen (HK), leading to the characteristic edema of HAE. Herein, we disclose the discovery and optimisation of novel small molecule PKa inhibitors leading to KVD900, a clinical candidate with positive phase 2 efficacy data as an oral on-demand treatment for HAE attacks. Starting from molecules containing highly basic P1 groups, which typically bind to Asp189 in the serine protease S1 pocket, we focussed on an approach to identify potent PKa inhibitors with reduced basicity which are likely to have greater potential for oral drug-like properties. Our discovery led to a series of monocyclic P1 binding groups, and particularly to the identification of the methoxypyridine P1 functionality, novel within the serine protease field. The favourable properties of this new P1 binding group, together with the optimisation of P4 and central core, led to potent, selective and oral PKa inhibitors. This will be a first-time presentation of the structure of KVD900 a potent (3 nM Ki), selective, orally bioavailable small molecule plasma kallikrein inhibitor.

Discovery of 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

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.