ABSTRACT
Leukotrienes are lipid mediators generated when arachidonic acid (AA) is metabolized by 5-lipoxygenase enzyme (5-LO). At the present time, leukotrienes are divided into cysteinyl leukotrienes (CysLTs) and leukotriene B4 (LTB4). CysLT and LTB4 act on different cell surface receptors, namely CysLT receptor and LTB4 receptor. Leukotrienes have potent pharmacological action on the airway. CysLTs exert potent bronchoconstrictor action whereas LTB4 exhibits chemotactic activity on neutrophils. Leukotriene action can be modulated by antagonizing leukotriene receptors as well as by inhibiting leukotriene synthesis. A lot of effort has gone into
5.1 Introduction .................................................................................................. 101 5.2 Leukotriene Biosynthesis .............................................................................. 102
5.2.1 5-Lipoxygenase-Activating Protein .................................................. 102 5.3 Leukotriene Receptors .................................................................................. 104
5.3.1 Receptors for CysLTs ........................................................................ 104 5.3.2 Receptors for LTB4 ........................................................................... 105
5.4 Leukotrienes in Asthma ............................................................................... 106 5.4.1 Cysteinyl Leukotrienes in Asthma ................................................... 106
5.4.1.1 CysLTs and Bronchoconstriction ....................................... 106 5.4.1.2 CysLTs and InŠammation .................................................. 107 5.4.1.3 CysLTs and Vascular Permeability .................................... 108
5.4.2 LTB4 in Asthma and COPD ............................................................. 108 5.5 Drug Discovery Efforts: Modulating Leukotriene Levels
and Leukotriene Function ............................................................................. 110 5.5.1 CysLT Receptor Antagonists ............................................................ 110
5.5.1.1 Clinical Evidence ............................................................... 112 5.5.2 BLT1 and BLT2 Receptor Antagonists .............................................. 114 5.5.3 FLAP Inhibitor ................................................................................. 116
5.6 Summary and Perspective ............................................................................ 119 References .............................................................................................................. 120
designing leukotriene receptor antagonists. CysLT receptor antagonist montelukast has become a drug. However, not much success has been achieved in designing LTB4 receptor antagonist. Synthesis of leukotrienes can be blocked using inhibitors of 5-LO as well as 5-lipoxygenase-activating protein (FLAP). 5-LO as a drug discovery target has been discussed in detail in Chapter 4. In this chapter, we will look into leukotriene receptor and FLAP as targets for airway inŠammatory diseases such as asthma and chronic obstructive pulmonary disease.
