1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides as potent factor Xa inhibitors. Part 3: Design, synthesis and SAR of orally bioavailable benzamidine-P4 inhibitors

Zhaozhong J Jia; Yanhong Wu; Wenrong Huang; Penglie Zhang; Yonghong Song; John Woolfrey; Uma Sinha; Ann E Arfsten; Susan T Edwards; Athiwat Hutchaleelaha; Stanley J Hollennbach; Joseph L Lambing; Robert M Scarborough; Bing-Yan Zhu

doi:10.1016/j.bmcl.2003.12.054

1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides as potent factor Xa inhibitors. Part 3: Design, synthesis and SAR of orally bioavailable benzamidine-P4 inhibitors

Bioorg Med Chem Lett. 2004 Mar 8;14(5):1229-34. doi: 10.1016/j.bmcl.2003.12.054.

Authors

Zhaozhong J Jia¹, Yanhong Wu, Wenrong Huang, Penglie Zhang, Yonghong Song, John Woolfrey, Uma Sinha, Ann E Arfsten, Susan T Edwards, Athiwat Hutchaleelaha, Stanley J Hollennbach, Joseph L Lambing, Robert M Scarborough, Bing-Yan Zhu

Affiliation

¹ Millennium Pharmaceuticals Inc., 256 East Grand Avenue, South San Francisco, CA 94080, USA. zjia@portola.com

PMID: 14980671
DOI: 10.1016/j.bmcl.2003.12.054

Abstract

Using N,N-dialkylated benzamidines as the novel P4 motifs, we have designed and synthesized a class of 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent and selective fXa inhibitors with significantly improved hydrophilicity and in vitro anticoagulant activity. These benzamidine-P4 fXa inhibitors have displayed excellent oral bioavailability and long half-life.

MeSH terms

Administration, Oral
Amides / administration & dosage
Amides / chemical synthesis*
Amides / metabolism
Animals
Antithrombin III / administration & dosage
Antithrombin III / chemical synthesis*
Antithrombin III / metabolism
Benzamidines / antagonists & inhibitors*
Benzamidines / metabolism
Biological Availability
Drug Design
Humans
Pyrazoles / administration & dosage
Pyrazoles / chemical synthesis*
Pyrazoles / metabolism
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Amides
Benzamidines
Pyrazoles
pyrazole
Antithrombin III