Design, synthesis and structure-activity relationships of benzoxazinone-based factor Xa inhibitors

Wenrong Huang; Penglie Zhang; Jingmei F Zuckett; Lingyan Wang; John Woolfrey; Yonghong Song; Zhaozhong J Jia; Lane A Clizbe; Ting Su; Katherine Tran; Brian Huang; Paul Wong; Uma Sinha; Gary Park; Andrea Reed; John Malinowski; Stanley J Hollenbach; Robert M Scarborough; Bing-Yan Zhu

doi:10.1016/s0960-894x(02)00927-7

Design, synthesis and structure-activity relationships of benzoxazinone-based factor Xa inhibitors

Bioorg Med Chem Lett. 2003 Feb 10;13(3):561-6. doi: 10.1016/s0960-894x(02)00927-7.

Affiliation

¹ Millennium Pharmaceuticals, Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA.

PMID: 12565972
DOI: 10.1016/s0960-894x(02)00927-7

Abstract

A series of benzoxazinone derivatives was designed and synthesized as factor Xa inhibitors. We demonstrated that the naphthyl moiety in the aniline-based compounds 1 and 2 can be replaced with benzene-fused heterobicycles and biaryls to give factor Xa inhibitors with improved trypsin selectivity. The P4 modifications lead to monoamidines which are moderately active. The benzoxazinones 41-45 are potent against factor Xa, retain the improved trypsin selectivity of the corresponding aniline-based compounds, and show strong antithrombotic effect dose responsively.

MeSH terms

Aniline Compounds / chemical synthesis
Aniline Compounds / pharmacology
Animals
Binding, Competitive / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design
Factor Xa Inhibitors*
In Vitro Techniques
Indicators and Reagents
Models, Molecular
Molecular Conformation
Oxazines / chemical synthesis*
Oxazines / pharmacology*
Rabbits
Structure-Activity Relationship
Thrombin / metabolism
Trypsin Inhibitors / chemical synthesis
Trypsin Inhibitors / pharmacology

Substances

Aniline Compounds
Factor Xa Inhibitors
Indicators and Reagents
Oxazines
Trypsin Inhibitors
Thrombin