title: Discovery of N-[2-hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (darexaban, YM150) as a potent and orally available factor Xa inhibitor.
abstract: Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound 1a that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of 1a without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 14i is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.
authors: Drug Discovery Research, Astellas Pharma Inc, 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. fukushi.hirayama@astellas.com
authors: Fukushi
authors: F
authors: Hirayama
authors: Hiroyuki
authors: H
authors: Koshio
authors: Tsukasa
authors: T
authors: Ishihara
authors: Shunichiro
authors: S
authors: Hachiya
authors: Keizo
authors: K
authors: Sugasawa
authors: Yuji
authors: Y
authors: Koga
authors: Norio
authors: N
authors: Seki
authors: Ryouta
authors: R
authors: Shiraki
authors: Takeshi
authors: T
authors: Shigenaga
authors: Yoshiyuki
authors: Y
authors: Iwatsuki
authors: Yumiko
authors: Y
authors: Moritani
authors: Kenichi
authors: K
authors: Mori
authors: Takeshi
authors: T
authors: Kadokura
authors: Tomihisa
authors: T
authors: Kawasaki
authors: Yuzo
authors: Y
authors: Matsumoto
authors: Shuichi
authors: S
authors: Sakamoto
authors: Shin-ichi
authors: S
authors: Tsukamoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D020134:Catalytic Domain; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D001381:Azepines; D001549:Benzamides; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D020719:Glucuronides; D015951:Factor Xa; C569750:darexaban