Discovery of BIRM 270: A New Class of Leukotriene Biosynthesis Inhibitors

Abstract

Several events in the late 1970s and early 1980s helped to shape the research agenda for pharmaceutical companies engaged in the search for a new generation of anti-inflammatory agents. The structural identity of the arachi- donic acid (AA) metabolite leukotriene B4 (LTB4) (Borgeat and Samuels- son, 1979) and the discovery that it was a potent neutrophil chemoattractant (Ford-Hutchinson et al., 1980) helped to elucidate how leukocytes migrate to a site of inflammation. In addition, the identification of leukotriene C4 (LTC4) as a component of slow reacting substance of anaphylaxis (SRS- A) demonstrated that arachidonic acid-derived substances were also potent bronchoconstrictors (Murphy and Hammarström, 1979; Corey et al., 1980; Sirois and Borgeat, 1980). Common to both classes of leukotrienes is the enzyme 5-lipoxygenase (5-LO) which introduces a molecule of oxygen at the C-5 position of AA followed by cyclization to the epoxide intermediate ITA4. Further reaction with a glutathione S-transferase yields the peptidyl LTs, LTC4 and its metabolites LTD4 and LTE4. Conversion of the epoxide by LTA4 hydrolase produces LTB4. Given that AA also serves as a substrate for the cyclooxygenase (CO) pathway to produce pro-inflammatory prostaglandins and thromboxane, interest was certainly reinforced in inhibiting one or both arms of what is often called the arachidonic acid cascade.