title: Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor.
abstract: Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.
authors.affiliation: Millennium Pharmaceuticals, Inc, South San Francisco, CA 94080, USA.
authors.forename: Penglie
authors.initials: P
authors.lastname: Zhang
authors.forename: Wenrong
authors.initials: W
authors.lastname: Huang
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Bao
authors.forename: Zhaozhong J
authors.initials: ZJ
authors.lastname: Jia
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Bauer
authors.forename: Erick A
authors.initials: EA
authors.lastname: Goldman
authors.forename: Gary D
authors.initials: GD
authors.lastname: Probst
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Song
authors.forename: Ting
authors.initials: T
authors.lastname: Su
authors.forename: Jingmei
authors.initials: J
authors.lastname: Fan
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Wenhao
authors.initials: W
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Woolfrey
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.forename: Paul W
authors.initials: PW
authors.lastname: Wong
authors.forename: Susan T
authors.initials: ST
authors.lastname: Edwards
authors.forename: Ann E
authors.initials: AE
authors.lastname: Arfsten
authors.forename: Lane A
authors.initials: LA
authors.lastname: Clizbe
authors.forename: James
authors.initials: J
authors.lastname: Kanter
authors.forename: Anjali
authors.initials: A
authors.lastname: Pandey
authors.forename: Gary
authors.initials: G
authors.lastname: Park
authors.forename: Athiwat
authors.initials: A
authors.lastname: Hutchaleelaha
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Lambing
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Hollenbach
authors.forename: Robert M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D008252:Macaca fascicularis; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats
chemical_list: D000925:Anticoagulants; D001549:Benzamides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D065427:Factor Xa Inhibitors; C000606913:KCNH2 protein, human; D011725:Pyridines; C543086:betrixaban; D015951:Factor Xa