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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

Davie, Rebecca L.; Edwards, Hannah J.; Evans, D. Michael; Hodgson, Simon T.; Stocks, Michael J.; Smith, Alun J.; Rushbrooke, Louise J.; Pethen, Stephen J.; Roe, Michael B.; Clark, David E.; McEwan, Paul A.; Hampton, Sally L.

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 Thumbnail


Authors

Rebecca L. Davie

Hannah J. Edwards

D. Michael Evans

Simon T. Hodgson

MICHAEL STOCKS MICHAEL.STOCKS@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry and Drug Discovery

Alun J. Smith

Louise J. Rushbrooke

Stephen J. Pethen

Michael B. Roe

David E. Clark

Paul A. McEwan

Sally L. Hampton



Abstract

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.

Citation

Davie, R. L., Edwards, H. J., Evans, D. M., Hodgson, S. T., Stocks, M. J., Smith, A. J., …Hampton, S. L. (2022). 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. Journal of Medicinal Chemistry, 65(20), 13629-13644. https://doi.org/10.1021/acs.jmedchem.2c00921

Journal Article Type Article
Acceptance Date Oct 17, 2022
Online Publication Date Oct 17, 2022
Publication Date Oct 17, 2022
Deposit Date Oct 26, 2022
Publicly Available Date Mar 29, 2024
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society (ACS)
Peer Reviewed Peer Reviewed
Volume 65
Issue 20
Pages 13629-13644
DOI https://doi.org/10.1021/acs.jmedchem.2c00921
Keywords Drug Discovery, Molecular Medicine
Public URL https://nottingham-repository.worktribe.com/output/12624689
Publisher URL https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00921

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