Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors

Isao Sakurada; Toshiya Endo; Katsuyoshi Hikita; Tomokazu Hirabayashi; Yoshitaka Hosaka; Yutaka Kato; Yoshitaka Maeda; Shigeki Matsumoto; Takashi Mizuno; Hiroshi Nagasue; Teruyuki Nishimura; Shunsuke Shimada; Mikihiko Shinozaki; Keiko Taguchi; Katsutoshi Takeuchi; Tooru Yokoyama; Alan Hruza; Paul Reichert; Ting Zhang; Harold B Wood; Kazunari Nakao; Shoji Furusako

doi:10.1016/j.bmcl.2017.03.002

Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2622-2628. doi: 10.1016/j.bmcl.2017.03.002. Epub 2017 Mar 6.

Authors

Isao Sakurada¹, Toshiya Endo², Katsuyoshi Hikita², Tomokazu Hirabayashi², Yoshitaka Hosaka², Yutaka Kato², Yoshitaka Maeda², Shigeki Matsumoto², Takashi Mizuno², Hiroshi Nagasue², Teruyuki Nishimura², Shunsuke Shimada², Mikihiko Shinozaki², Keiko Taguchi², Katsutoshi Takeuchi², Tooru Yokoyama², Alan Hruza³, Paul Reichert³, Ting Zhang⁴, Harold B Wood⁴, Kazunari Nakao², Shoji Furusako²

Affiliations

¹ Discovery Research, Mochida Pharmaceutical Co. Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan. Electronic address: isao.sakurada@mochida.co.jp.
² Discovery Research, Mochida Pharmaceutical Co. Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan.
³ Department of Structural Chemistry, Merck Research Laboratories, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
⁴ Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

PMID: 28408226
DOI: 10.1016/j.bmcl.2017.03.002

Abstract

Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.

Keywords: Aminobenzisoxazole; Anticoagulant; Azabicyclic ring; Factor IXa inhibitor; Structure based drug design.

MeSH terms

Animals
Binding Sites
Blood Coagulation / drug effects
Crystallography, X-Ray
Dogs
Drug Design
Drug Evaluation, Preclinical
Factor IXa / antagonists & inhibitors*
Factor IXa / metabolism
Half-Life
Humans
Inhibitory Concentration 50
Isoxazoles / chemistry*
Isoxazoles / metabolism
Isoxazoles / pharmacology
Molecular Dynamics Simulation
Partial Thromboplastin Time
Protein Structure, Tertiary
Prothrombin Time
Rats
Structure-Activity Relationship

Substances

Isoxazoles
Factor IXa