3KL6

Discovery of Tetrahydropyrimidin-2(1H)-one derivative TAK-442: A potent, selective and orally active factor Xa inhibitor

Summary for 3KL6

• Entry DOI: 10.2210/pdb3kl6/pdb
• Descriptor: Coagulation Factor X heavy chain, Coagulation Factor X light chain, 1-(1-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperidin-4-yl)tetrahydropyrimidin-2(1H)-one, ... (6 entities in total)
• Functional Keywords: coagulation factor xa, blood coagulation, cleavage on pair of basic residues, disulfide bond, egf-like domain, gamma-carboxyglutamic acid, glycoprotein, hydrolase, hydroxylation, protease, secreted, serine protease, zymogen
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 2
• Total formula weight: 34238.49

Authors

Aertgeerts, K. (deposition date: 2009-11-06, release date: 2009-12-01, Last modification date: 2024-11-20)

Primary citation

Fujimoto, T.,Imaeda, Y.,Konishi, N.,Hiroe, K.,Kawamura, M.,Textor, G.P.,Aertgeerts, K.,Kubo, K.
Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor.
J.Med.Chem., 53:3517-3531, 2010

PubMed Abstract: Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.

PubMed: 20355714
DOI: 10.1021/jm901699j

Experimental method

X-RAY DIFFRACTION (1.45 Å)