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

Dominique Potin; 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

doi:10.1016/j.bmcl.2004.12.007

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.

Affiliation

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.

MeSH terms

Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Drug Design
HeLa Cells
Humans
Hydantoins / chemical synthesis*
Hydantoins / pharmacology
Inflammation / drug therapy
Inhibitory Concentration 50
Intercellular Adhesion Molecule-1 / chemistry
Lymphocyte Function-Associated Antigen-1 / chemistry
Lymphocyte Function-Associated Antigen-1 / drug effects*
Molecular Conformation
Protein Binding / drug effects
Structure-Activity Relationship

Substances

Bridged Bicyclo Compounds, Heterocyclic
Hydantoins
Lymphocyte Function-Associated Antigen-1
Intercellular Adhesion Molecule-1