Richard A. Craig

Design of inhibitors of leukotriene biosynthesis and their therapeutic potential

Leukotrienes (LT) are biosynthetic products derived from arachidonic acid. Investigational drugs which inhibit the biosynthesis of LT or block the actions of LT at their receptors have shown therapeutic benefit in asthmatics. A new series of 2-quinolylmethoxyphenylalkyliminoxyalkylcarboxylates was discovered which blocked LT biosynthesis in intact cells but did not inhibit 5-LO catalysis. The mechanism of LT inhibition likely resulted from interfering with five-lipoxygenase activating protein (FLAP). The spatial arrangement and stereochemistry of groups proved important for inhibitory activity. A-93 178.5 is an optimized leukotriene inhibitor with potent oral activity in several animal models. Leukotrienes (LT) are biosynthetic products derived from arachidonic acid (AA).(ref. 1) AA is released from esterified phopholipids in response to receptor mediated intracellular influx of Ca+2. Five lipoxygenase activating protein (FLAP) is proposed to act as a carrier protein which presents AA to the 5- lipoxygenase (5-LO) enzyme resulting in activation of oxidative catalysis.(ref. 2) 5-LO catalyses two transformations, the addition of molecular oxygen to provide the 5-hydroperoxide intermediate (5-HETE) which is subsequently dehydrated to the reactive epoxide LTA4. Two distinct pathways of LTA4 metabolism provide the other leukotrienes as shown in Figure 1. LTB4 has potent activity as a proinflammatory mediator involved in inflammatory cell recruitment, leukocyte activation and adherence of myeloid cells. The cysteinyl LT are very potent mediators of airway smooth muscle contraction, vascular permeability and airway mucus secretion. Studies of the properties and function of LT since their discovery clearly indicated them to be naturally occurring mediators of pathophysiology associated with the symptoms of asthma.(ref. 3) Asthma afflicts over 13 million people in the United States and the incidence, morbidity and mortality has been increasing which points to the fact that current therapy is inadequate. The primary symptoms of asthma are characterized by episodic reversible airway constriction, airway hyperresponsiveness to various stimuli and chronic inflammation. Research to define appropriate investigational drugs to clearly establish the role of leukotrienes in asthma has proven to be very challenging.(ref. 4) At this time, several agents have progressed through clinical trials and the results confirm that blocking the effects of LT results in a significant therapeutic benefit. Two therapeutic approaches have been successful: inhibiting the biosynthesis of LT and blocking the action of leukotrienes at their respective receptors. LT therapy in asthma has demonstrated immediate airway improvement as a result of preventing the actions of ongoing LT pathology. The degree of improvement in chronic asthmatics was comparable to established therapies which are mechanistically different. The airway improvement was additive with combined treatment with beta-agonists or inhaled steroids. Reduced use of beta-agonists and inhaled steroids was another benefit observed. Anti-LT therapy provides the first mechanistically new therapy for asthma in over twenty years. It remains to be determined whether a specific mode of LT intervention: 5-LO inhibitors, FLAP inhibitors, LTD4 receptor antagonists or LTB4 antagonists will provide distinguishable therapeutic properties. In addition, evaluation of anti-LT drugs in other disorders with LT involvement such as inflammatory bowel disease, rheumatoid arthritis and chronic rhinitis will likely follow. The chronic safety for specific classes of anti-LT drugs over longer periods of therapy also remains to be established.