Development of a novel class of potent and selective FIXa inhibitors

Ting Zhang; Patrick Andre; Thomas J Bateman; Yi-Heng Chen; Kunal Desai; Kenneth Ellsworth; Wayne M Geissler; Liangqin Guo; Alan Hruza; Tianying Jian; Dongfang Meng; Dann L Parker Jr; Xiaoxia Qian; Paul Reichert; Edward C Sherer; Min Shu; Cameron J Smith; Lisa M Sonatore; Richard Tschirret-Guth; Andrew F Nolting; Robert Orr; Louis-Charles Campeau; Kazuto Araki; Teruyuki Nishimura; Isao Sakurada; Harold B Wood

doi:10.1016/j.bmcl.2015.04.057

Development of a novel class of potent and selective FIXa inhibitors

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4945-4949. doi: 10.1016/j.bmcl.2015.04.057. Epub 2015 Apr 29.

Authors

Ting Zhang¹, Patrick Andre², Thomas J Bateman³, Yi-Heng Chen⁴, Kunal Desai², Kenneth Ellsworth⁵, Wayne M Geissler⁵, Liangqin Guo⁴, Alan Hruza⁶, Tianying Jian⁴, Dongfang Meng⁴, Dann L Parker Jr⁴, Xiaoxia Qian⁴, Paul Reichert⁶, Edward C Sherer⁷, Min Shu⁴, Cameron J Smith⁴, Lisa M Sonatore⁵, Richard Tschirret-Guth³, Andrew F Nolting⁸, Robert Orr⁸, Louis-Charles Campeau⁸, Kazuto Araki⁹, Teruyuki Nishimura⁹, Isao Sakurada⁹, Harold B Wood⁴

Affiliations

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. Electronic address: ting_zhang3@merck.com.
² Department of Cardiometabolic Disease, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
³ Department of Pharmacokinetics, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
⁴ Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
⁵ Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
⁶ Department of Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
⁷ Department of Chemistry Modeling and Informatics, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
⁸ Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
⁹ Discovery Research, Mochida Pharmaceutical Co., LTD, 7, Yotsuya 1-Chome, Shinjuku-ku, Tokyo 160-8515, Japan.

PMID: 25978966
DOI: 10.1016/j.bmcl.2015.04.057

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.

Keywords: Benzimidazole; FIXa inhibitor; Structure based drug design; TGA.

MeSH terms

Administration, Oral
Amines / chemical synthesis
Amines / chemistry
Amines / pharmacology*
Animals
Biological Availability
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Factor IXa / antagonists & inhibitors*
Factor IXa / metabolism
Humans
Models, Molecular
Molecular Structure
Rats
Structure-Activity Relationship

Substances

Amines
Enzyme Inhibitors
Factor IXa