Design, synthesis and SAR of novel ethylenediamine and phenylenediamine derivatives as factor Xa inhibitors

Kenji Yoshikawa; Toshiharu Yoshino; Yoshihiro Yokomizo; Kouichi Uoto; Hiroyuki Naito; Katsuhiro Kawakami; Akiyoshi Mochizuki; Tsutomu Nagata; Makoto Suzuki; Hideyuki Kanno; Makoto Takemura; Toshiharu Ohta

doi:10.1016/j.bmcl.2011.01.132

Design, synthesis and SAR of novel ethylenediamine and phenylenediamine derivatives as factor Xa inhibitors

Bioorg Med Chem Lett. 2011 Apr 1;21(7):2133-40. doi: 10.1016/j.bmcl.2011.01.132. Epub 2011 Feb 1.

Authors

Kenji Yoshikawa¹, Toshiharu Yoshino, Yoshihiro Yokomizo, Kouichi Uoto, Hiroyuki Naito, Katsuhiro Kawakami, Akiyoshi Mochizuki, Tsutomu Nagata, Makoto Suzuki, Hideyuki Kanno, Makoto Takemura, Toshiharu Ohta

Affiliation

¹ R&D Division, Daiichi Sankyo Co, Ltd, 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. [email protected]

PMID: 21345673
DOI: 10.1016/j.bmcl.2011.01.132

Abstract

We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30 h which showed both good in vitro activity (fXa IC(50) = 2.2 nM, PTCT2 = 3.9 μM) and in vivo antithrombotic efficacy.

MeSH terms

Crystallography, X-Ray
Drug Design
Factor Xa Inhibitors*
Models, Molecular
Serine Proteinase Inhibitors / chemical synthesis
Serine Proteinase Inhibitors / chemistry*
Serine Proteinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Factor Xa Inhibitors
Serine Proteinase Inhibitors