De novo design, synthesis, and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold

  • Bioorg Med Chem Lett. 2005 Feb 15;15(4):1161-4. doi: 10.1016/j.bmcl.2004.12.007.
Dominique Potin  1 ,  Michele Launay ,  Eric Nicolai ,  Maud Fabreguette ,  Patrice Malabre ,  François Caussade ,  Dominique Besse ,  Stacey Skala ,  Dawn K Stetsko ,  Gordon Todderud ,  Brett R Beno ,  Daniel L Cheney ,  Chiehying J Chang ,  Steven Sheriff ,  Diane L Hollenbaugh ,  Joel C Barrish ,  Edwin J Iwanowicz ,  Suzanne J Suchard ,  T G Murali Dhar
Affiliations
  • 1. Cerep, 128, rue Danton, 92500 Rueil-Malmaison, France.
PMID: 15686933 DOI: 10.1016/j.bmcl.2004.12.007
Abstract

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.