STRATEGIES IN THE DESIGN OF PEPTIDOLEUKOTRIENE ANTAGONISTS

The research of the last two decades in the field of SRS-A and peptido leukotriene (pLT) antagonists has provided information for the design of potent pLT antagonists, which share some or all of the following st ructural elements: (1) a lipophilic anchor, which fits into the lipoph ilic pocket of the LTD4 receptor; (2) a central lipophilic unit mimick ing the tetraene system of LTD4; (3) one or two acidic groups, as mimi cs of the cysteinyl-glycine unit and/or the carboxylic group in the ei cosanoid backbone of LTD4; (4) spacers connecting these elements. Pote nt pLT antagonists lacking a second polar binding group compensate by stronger interaction in other regions of the receptor. Identification of pLT antagonists is based on lead optimisation, preparation of pLT a nalogs and on the knowledge of the pLT receptor.