Design, synthesis, and SAR of monobenzamidines and aminoisoquinolines as factor Xa inhibitors

Penglie Zhang; Jingmei F Zuckett; John Woolfrey; Katherine Tran; Brian Huang; Paul Wong; Uma Sinha; Gary Park; Andrea Reed; John Malinowski; Stan Hollenbach; Robert M Scarborough; Bing-Yan Zhu

doi:10.1016/s0960-894x(02)00234-2

Design, synthesis, and SAR of monobenzamidines and aminoisoquinolines as factor Xa inhibitors

Bioorg Med Chem Lett. 2002 Jun 17;12(12):1657-61. doi: 10.1016/s0960-894x(02)00234-2.

Authors

Penglie Zhang¹, Jingmei F Zuckett, John Woolfrey, Katherine Tran, Brian Huang, Paul Wong, Uma Sinha, Gary Park, Andrea Reed, John Malinowski, Stan Hollenbach, Robert M Scarborough, Bing-Yan Zhu

Affiliation

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

PMID: 12039584
DOI: 10.1016/s0960-894x(02)00234-2

Abstract

Monoamidine FXa inhibitors 3 were designed and synthesized. SAR studies and molecular modeling led to the design of conformationally constrained diaryl ethers 4 and 5, as well as benzopyrrolidinone 7 as potent FXa inhibitors. The monoamidines show high efficacy in a DVT model, but lack desirable oral bioavailability. The benzopyrrolidinone-based aminoisoquinolines 8 do not show significant improvement in oral bioavailability.

MeSH terms

Administration, Oral
Animals
Benzamidines / chemical synthesis*
Benzamidines / chemistry
Benzamidines / pharmacokinetics
Benzamidines / pharmacology*
Biological Availability
Drug Design
Factor Xa Inhibitors*
Isoquinolines / chemical synthesis*
Isoquinolines / chemistry
Isoquinolines / pharmacokinetics
Isoquinolines / pharmacology*
Rats
Rats, Sprague-Dawley
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / chemistry
Serine Proteinase Inhibitors / pharmacokinetics
Serine Proteinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Benzamidines
Factor Xa Inhibitors
Isoquinolines
Serine Proteinase Inhibitors