Montelukast Sodium Singulair

Structural Formula

Ball-and-Stick Model

Ball-and-Stick Model


■ Carbon = Hydrogen A = Oxygen A = Chlorine A = Nitrogen Si = Sulfur

Year of discovery: 1991; Year of introduction: 1998 (Merck); Drug category: Oral leukotriene receptor antagonist; Main uses: Treatment of asthma and to relieve symptoms of seasonal allergies; Related drugs: Zafirlukast (Accolate), Pranlukast (Onon).

Montelukast sodium is a synthetic antagonist of the cysteinyl leukotriene receptor which has proven efficacious in the treatment of asthma.

The severity of asthma varies from mild to life-threatening. Narrowing of the airways is induced by the combination of inflammation of the bronchial tubes and muscular constriction. It can be triggered by hypersensitivity to allergens, irritants, infection or nerve signals.

Receptors on the surface of the airways bind mediators called cysteinyl leukotrienes (CysLT), small molecules produced in response to irritants. Upon binding to the target receptors, cysteinyl leukotrienes induce bronchial and smooth muscle contraction and enhance production of mucus in excess of the amount normally required to clear foreign particles. Leukotrienes have been shown to be inflammatory and to be involved in asthmatic and allergic reactions. A recent treatment of asthma is based on blocking the proinflammatory binding of leukotrienes to their receptors.

Cysteinyl leukotrienes were first detected as bronchoconstrictive factors in guinea pigs that had been sensitized with cobra venom (by Australian physiologist C. H. Kellaway in 1938). Since these factors were observed to cause a slow and prolonged contraction of muscles, they were termed as slow-reacting substances of anaphylaxis (SRS-A). The chemical nature of SRS-A was uncovered only years later, when Bengt Samuelsson at the Karolinska Institute discovered that SRS-A contained a lipid subunit derived from arachidonic acid. Because these substances could be formed in vitro from leukocytes

(white blood cells), they were termed leukotrienes. The exact chemical structure of all the leukotrienes was determined by Samuelsson and the Corey group at Harvard. An efficient chemical synthesis of the leukotrienes was developed that was essential not only to the proof of structure but also to making these unstable and very rare compounds available for biological studies. With the availability of synthetic leukotrienes, investigation began to find molecules that either block leukotriene biosynthesis or receptor binding.

Among the innumerable CysLT antagonists made and investigated, the most widely used today is the sodium salt of montelukast, which is produced by Merck and Co. and marketed as Singulair. Given orally, it is bioavailable, potent and safe for many asthmatics and can be used with bronchodilating (3-agonists (see salmeterol). Singulair is also effective in the treatment of allergic rhinitis. Since the approval of Singulair in 1998, sales have climbed to over $2 billion per year.1,2

An earlier leukotriene receptor antagonist, zafirlukast, introduced as Accolate in 1996 by AstraZeneca, is less widely used.

1. Journal of Drug Evaluation: Respiratory Medicine 2002, 1, 53-88; 2. Expert Opin. Pharmaco. 2004, 5, 679-686; Refs. p. 81

1. Journal of Drug Evaluation: Respiratory Medicine 2002, 1, 53-88; 2. Expert Opin. Pharmaco. 2004, 5, 679-686; Refs. p. 81

Zafirlukast (Accolate

Zafirlukast (Accolate

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