Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors. Part 1: P(1) structure-activity relationships of the substituted 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides

Zhaozhong J Jia; Yanhong Wu; Wenrong Huang; Erick Goldman; Penglie Zhang; John Woolfrey; Paul Wong; Brian Huang; Uma Sinha; Gary Park; Andrea Reed; Robert M Scarborough; Bing-Yan Zhu

doi:10.1016/s0960-894x(02)00239-1

Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors. Part 1: P(1) structure-activity relationships of the substituted 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides

Bioorg Med Chem Lett. 2002 Jun 17;12(12):1651-5. doi: 10.1016/s0960-894x(02)00239-1.

Authors

Zhaozhong J Jia¹, Yanhong Wu, Wenrong Huang, Erick Goldman, Penglie Zhang, John Woolfrey, Paul Wong, Brian Huang, Uma Sinha, Gary Park, Andrea Reed, Robert M Scarborough, Bing-Yan Zhu

Affiliation

¹ Medicinal Chemistry Department, Millennium Pharmaceuticals, Inc., 256 East Grand Ave, South San Francisco, CA 94080, USA. [email protected]

PMID: 12039583
DOI: 10.1016/s0960-894x(02)00239-1

Abstract

Based on DuPont Pharmaceuticals' monobenzamidine lead structure SN429, we have designed the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as a novel series of non-basic factor Xa inhibitors. We have discovered that the displacement of the benzamidine moiety with substituted 2-naphthyl structures not only results in highly potent factor Xa inhibitors, but also significantly increases their enzyme specificity and oral bioavailability.

MeSH terms

Amides / chemistry
Animals
Drug Design
Factor Xa Inhibitors*
Pyrazoles / chemical synthesis*
Pyrazoles / chemistry
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology*
Rats
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / chemistry
Serine Proteinase Inhibitors / pharmacokinetics
Serine Proteinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Amides
Factor Xa Inhibitors
Pyrazoles
Serine Proteinase Inhibitors