Small molecules useful in the treatment of inflammatory disease

Abstract

A series of substituted N³-phenylhydantoins are claimed as the first small molecule, non-peptidic antagonists of the binding of intercellular adhesion molecules such as ICAM-1 with the leukointegrin LFA-1. The Boehringer-Ingelheim investigators describe the synthesis of 278 analogues, including a variety with substituents at each ring position as well as several thiocarbonyl variants. All compounds are evaluated for their ability to block LFA-1/ICAM-1 binding; supplementary biochemical data demonstrate the ability of representative compounds to block cell adhesion and aggregation, as well as the mixed lymphocyte reaction (MLR). Cellular toxicity data (MTT uptake) are included, and in vivo data in an allogeneic cell transplantation assay are described for several antagonists. LFA/ICAM antagonists may find utility in the treatment of a variety of inflammatory or immune disorders.

• adhesion molecule
• anti-inflammatory
• hydantoin
• immunosuppressant
• intercellular adhesion molecules (ICAM)
• leukointegrin
• LFA-1