title: Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor.
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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 2-17-85, Jusohomachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Imaeda
authors.forename: Noriko
authors.initials: N
authors.lastname: Konishi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hiroe
authors.forename: Masaki
authors.initials: M
authors.lastname: Kawamura
authors.forename: Garret P
authors.initials: GP
authors.lastname: Textor
authors.forename: Kathleen
authors.initials: K
authors.lastname: Aertgeerts
authors.forename: Keiji
authors.initials: K
authors.lastname: Kubo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001760:Bleeding Time; D055808:Drug Discovery; D065427:Factor Xa Inhibitors; D000882:Haplorhini; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010599:Pharmacokinetics; D011744:Pyrimidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011744:Pyrimidinones; C505709:tetrahydropyrimidinone