title: Development of a novel class of potent and selective FIXa inhibitors.
abstract: Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. Electronic address: ting_zhang3@merck.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Andre
authors.affiliation: Department of Pharmacokinetics, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bateman
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Yi-Heng
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Kunal
authors.initials: K
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ellsworth
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Geissler
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Liangqin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Hruza
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Tianying
authors.initials: T
authors.lastname: Jian
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Meng
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Dann L
authors.initials: DL
authors.lastname: Parker
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qian
authors.affiliation: Department of Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Reichert
authors.affiliation: Department of Chemistry Modeling and Informatics, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Sherer
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shu
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Smith
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sonatore
authors.affiliation: Department of Pharmacokinetics, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Tschirret-Guth
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Nolting
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Orr
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Campeau
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., LTD, 7, Yotsuya 1-Chome, Shinjuku-ku, Tokyo 160-8515, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Araki
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., LTD, 7, Yotsuya 1-Chome, Shinjuku-ku, Tokyo 160-8515, Japan.
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., LTD, 7, Yotsuya 1-Chome, Shinjuku-ku, Tokyo 160-8515, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Sakurada
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Harold B
authors.initials: HB
authors.lastname: Wood
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015949:Factor IXa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D015949:Factor IXa
keywords: Benzimidazole; FIXa inhibitor; Structure based drug design; TGA