8A3Q

Human Plasma Kallekrein in complex with 14W

Summary for 8A3Q

• Entry DOI: 10.2210/pdb8a3q/pdb
• Descriptor: Plasma kallikrein, UNKNOWN LIGAND, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, serine-like protease, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 29782.66

Authors

McEwan, P.A. (deposition date: 2022-06-08, release date: 2022-11-02, Last modification date: 2024-10-09)

Primary citation

Davie, R.L.,Edwards, H.J.,Evans, D.M.,Hodgson, S.T.,Stocks, M.J.,Smith, A.J.,Rushbrooke, L.J.,Pethen, S.J.,Roe, M.B.,Clark, D.E.,McEwan, P.A.,Hampton, S.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.
J.Med.Chem., 65:13629-13644, 2022

PubMed 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.

PubMed: 36251573
DOI: 10.1021/acs.jmedchem.2c00921

Experimental method

X-RAY DIFFRACTION (1.801 Å)