Leukotriene modifiers: novel therapeutic opportunities in asthma.
Cysteinyl leukotrienes (Cys-LT) are powerful proinflammatory autacoids that cause long-lasting bronchoconstriction, plasma leakage, increased mucus production; their biological activity suggests a prominent role in the etiopathology of asthma and several Cys-LT receptor antagonists and synthetase inhibitors have been developed as new antiasthmatic drugs. Zafirlukast was discovered by a mechanism-based approach to drug discovery; early structure-activity relationship analyses of the prototype SRS-A antagonist FPL-55712, lead to the identification of an indole-containing lead compound that was more specific than FPL-55712. Modifications were made on the lipid-like tail, indole backbone and acidic head region of this lead compound, resulting in potent and selective leukotriene receptor antagonists such as ICI-198615 and 204219 (zafirlukast). On the basis of successful results in preclinical asthma models, zafirlukast was recommended for clinical development and became the first leukotriene-modifier to be approved for the treatment of asthma. Leukotriene biosynthesis inhibitors (LSI) also represent a promising approach to the treatment of asthma and may theoretically provide a broader protection than Cys-LT receptor antagonists by inhibition of the synthesis of the two major leukotrienes, the Cys-LT and the chemotactic LTB4. The LSI BAY X-1005 is the result of a broad chemistry program that identified 15-HETE as an endogenous inhibitor of leukotriene synthesis and REV 5901 as a lead prototypic quinoline-based 5-lipoxygenase (5-LO) inhibitor. Clinical studies demonstrated the effectiveness of BAY X-1005 in experimental conditions such as allergen provocation and cold-air induced asthma. However, no consistent treatment effect in the overall asthma population (mild to moderately severe asthmatics) lead to discontinuation of its development.
Buccellati
Carola
C
Centro di Farmacologia Cardiopolmonare Sperimentale, Dip. of Pharmacol. Sciences, School of Pharmacy, Univ. of Milan, Italy.
Fumagalli
Francesca
F
Viappiani
Serena
S
Folco
Giancarlo
G
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D020024:Leukotriene Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D015289:Leukotrienes / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology; D048448:Phenylcarbamates; D013189:SRS-A / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000737:chemistry* / Q000494:pharmacology*
D018927:Anti-Asthmatic Agents; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D048448:Phenylcarbamates; D013189:SRS-A; D013449:Sulfonamides; D014105:Tosyl Compounds; C062735:zafirlukast