Strategies in the design of peptidoleukotriene antagonists.

Abstract

The research of the last two decades in the field of SRS-A and peptidoleukotriene (pLT) antagonists has provided information for the design of potent pLT antagonists, which share some or all of the following structural elements: (1) a lipophilic anchor, which fits into the lipophilic pocket of the LTD4 receptor; (2) a central lipophilic unit mimicking the tetraene system of LTD4; (3) one or two acidic groups, as mimics of the cysteinyl-glycine unit and/or the carboxylic group in the eicosanoid backbone of LTD4; (4) spacers connecting these elements. Potent 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 analogs and on the knowledge of the pLT receptor.