title: Development of a novel tricyclic class of potent and selective FIXa inhibitors.
abstract: Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. Electronic address: dongfang-meng@merck.com.
authors: Dongfang
authors: D
authors: Meng
authors: Department of Cardiometabolic Disease, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Patrick
authors: P
authors: Andre
authors: Department of Pharmacokinetics, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Thomas J
authors: TJ
authors: Bateman
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Richard
authors: R
authors: Berger
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Yi-Heng
authors: YH
authors: Chen
authors: Department of Cardiometabolic Disease, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Kunal
authors: K
authors: Desai
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Sunita
authors: S
authors: Dewnani
authors: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Kenneth
authors: K
authors: Ellsworth
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Daming
authors: D
authors: Feng
authors: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Wayne M
authors: WM
authors: Geissler
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Liangqin
authors: L
authors: Guo
authors: Department of Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Alan
authors: A
authors: Hruza
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Tianying
authors: T
authors: Jian
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Hong
authors: H
authors: Li
authors: Department of Cardiometabolic Disease, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Joe
authors: J
authors: Metzger
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Dann L
authors: DL
authors: Parker
authors: Department of Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Paul
authors: P
authors: Reichert
authors: Department of Chemistry Modeling and Informatics, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Edward C
authors: EC
authors: Sherer
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Cameron J
authors: CJ
authors: Smith
authors: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Lisa M
authors: LM
authors: Sonatore
authors: Department of Pharmacokinetics, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Richard
authors: R
authors: Tschirret-Guth
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Jane
authors: J
authors: Wu
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Jiayi
authors: J
authors: Xu
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Ting
authors: T
authors: Zhang
authors: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Louis-Charles
authors: LC
authors: Campeau
authors: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Robert
authors: R
authors: Orr
authors: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Marc
authors: M
authors: Poirier
authors: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Jamie
authors: J
authors: McCabe-Dunn
authors: Discovery Research, Mochida Pharmaceutical Co., LTD, 7, Yotsuya 1-Chome, Shinjuku-ku, Tokyo 160-8515, Japan.
authors: Kazuto
authors: K
authors: Araki
authors: Discovery Research, Mochida Pharmaceutical Co., LTD, 7, Yotsuya 1-Chome, Shinjuku-ku, Tokyo 160-8515, Japan.
authors: Teruyuki
authors: T
authors: Nishimura
authors: Discovery Research, Mochida Pharmaceutical Co., LTD, 7, Yotsuya 1-Chome, Shinjuku-ku, Tokyo 160-8515, Japan.
authors: Isao
authors: I
authors: Sakurada
authors: Discovery Research, Mochida Pharmaceutical Co., LTD, 7, Yotsuya 1-Chome, Shinjuku-ku, Tokyo 160-8515, Japan.
authors: Tomokazu
authors: T
authors: Hirabayashi
authors: Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
authors: Harold B
authors: HB
authors: Wood
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015949:Factor IXa / Q000037:antagonists & inhibitors*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D015949:Factor IXa
keywords: Benzimidazole; FIXa inhibitor; Quninazolinone; Structure based drug design; TGA