Synthesis and in vitro biological evaluation of aryl boronic acids as potential inhibitors of factor XIa

Tsvetelina I Lazarova; Lei Jin; Michael Rynkiewicz; Joan C Gorga; Frank Bibbins; Harold V Meyers; Robert Babine; James Strickler

doi:10.1016/j.bmcl.2006.07.043

Synthesis and in vitro biological evaluation of aryl boronic acids as potential inhibitors of factor XIa

Bioorg Med Chem Lett. 2006 Oct 1;16(19):5022-7. doi: 10.1016/j.bmcl.2006.07.043. Epub 2006 Jul 28.

Authors

Tsvetelina I Lazarova¹, Lei Jin, Michael Rynkiewicz, Joan C Gorga, Frank Bibbins, Harold V Meyers, Robert Babine, James Strickler

Affiliation

¹ Medicinal Chemistry, Daiichi Asubio Medical Research Laboratories, LLC, One Kendall Square, Building 700, Cambridge, MA 02139, USA. tlazarova@medchempartners.com

PMID: 16876411
DOI: 10.1016/j.bmcl.2006.07.043

Abstract

A series of functionalized aryl boronic acids were synthesized and evaluated as potential inhibitors of factor XIa. Crystal structures of the protein-inhibitor complexes led to the design and synthesis of second generation compounds showing single digit micromolar inhibition against FXIa and selectivity against thrombin, trypsin, and FXa.

MeSH terms

Anticoagulants / chemical synthesis*
Anticoagulants / pharmacology
Binding Sites
Boronic Acids / chemical synthesis*
Boronic Acids / pharmacology*
Crystallography, X-Ray
Drug Design
Factor XIa / antagonists & inhibitors*
Humans
Inhibitory Concentration 50
Protein Binding
Protein Conformation
Serine Proteinase Inhibitors / chemical synthesis
Serine Proteinase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Anticoagulants
Boronic Acids
Serine Proteinase Inhibitors
Factor XIa