Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors incorporating substituted biphenyl P4 motifs

Penglie Zhang; Liang Bao; Jingmei F Zuckett; Erick A Goldman; Zhaozhong J Jia; Ann Arfsten; Susan Edwards; Uma Sinha; Athiwat Hutchaleelaha; Gary Park; Joseph L Lambing; Stanley J Hollenbach; Robert M Scarborough; Bing-Yan Zhu

doi:10.1016/j.bmcl.2003.11.079

Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors incorporating substituted biphenyl P4 motifs

Bioorg Med Chem Lett. 2004 Feb 23;14(4):983-7. doi: 10.1016/j.bmcl.2003.11.079.

Authors

Penglie Zhang¹, Liang Bao, Jingmei F Zuckett, Erick A Goldman, Zhaozhong J Jia, Ann Arfsten, Susan Edwards, Uma Sinha, Athiwat Hutchaleelaha, Gary Park, Joseph L Lambing, Stanley J Hollenbach, Robert M Scarborough, Bing-Yan Zhu

Affiliation

¹ Millennium Pharmaceuticals, Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA. penglie.zhang@mpi.com

PMID: 15013006
DOI: 10.1016/j.bmcl.2003.11.079

Abstract

Anthranilamides 4 and 5 were designed and synthesized as selective and orally bioavailable factor Xa inhibitors. Structural modifications aimed at lowering their lipophilicity were performed at the central phenyl ring and at the S4 binding biphenyl region by incorporating water solublizing substituents. The resulting compounds (e.g., 7, 8, 14, 30a, and 32b) are highly potent in vitro, and show improved activity in human plasma-based thrombin generation assay.

MeSH terms

Administration, Oral
Amides / chemical synthesis*
Amides / pharmacology*
Animals
Biological Availability
Drug Design
Drug Evaluation, Preclinical
Factor Xa Inhibitors*
Humans
Molecular Structure
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Thrombosis / drug therapy
Thrombosis / prevention & control
ortho-Aminobenzoates / chemical synthesis*
ortho-Aminobenzoates / pharmacology*

Substances

Amides
Factor Xa Inhibitors
ortho-Aminobenzoates