Structural Requirements for Leukotriene CysLT1 Receptor Ligands

Leukotriene CysLT1 receptor antagonists (also known as LfD4 antagonists) are among the most promising antiasthmatic agents currently under investigation. For the last 20 years there are many thousands of compounds prepared as CysLT1 receptor antagonists and several of them have advanced to the clinical practice. The diverse chemical structures of CysLT1 antagonists pose considerable difficulty in the identification of structural determinants for their activity. This review summarizes the structural modifications within each individual class of compounds and derives the general structural requirements for CysLT1 antagonistic activity. Computer-aided rational design of CysL T1 antagonists have been thoroughly analyzed and a new pharmacophoric model is presented to accommodate almost all SAR data experimentally observed. Since a stable and selective CysLT1 receptor agonist would be a very useful pharmacological tool, especially for the characterization of receptor subtypes, the SARs of CysLT1 agonists have also been discussed in the present paper. These information are also important for the understanding of ligand recognition of the CysLT1 receptor.