Antiasthmatics – Singulair
The newest therapy available for the treatment of asthma arises from the recognition of the role of the leukotrienes in the initiation and propagation of airway inflammation. Merck’s montelukast sodium (trademark Singulair) is an antagonist of leukotriene receptors.
As early as 1938, Australian physiologist Charles H. Kellaway isolated a slow-reacting substance anaphylaxis (SRS-A) after he sensitized guinea pigs with cobra venom. SRS-A was the active principle that led to a slow, prolonged contractile response of the animal’s intestinal muscles. Because SRS-As are formed in only trace amounts and are intrinsically unstable, their identities remained unknown for four decades. By 1979, Bengt I. Samuelsson’s group at the Karolinska Institute in Stockholm, Sweden, identified one of the essential components of SRS-A (leukotriene E; LTE), consisting of the amino acid cysteine linked to a 20-carbon fatty acid. The realization shed light on the structure of SRS-A, but even at that point there were many possibilities, including approximately 128 possible stereo-chemical structures. In 1979, Elias J. Corey at Harvard University and coworkers reported a stereospecific synthesis of all leukotrienes and, in collaboration with Samuelsson, demonstrated functional identity between synthetic and the natural leukotriene C4 (LTC4). Subsequently, groups led by Samuelsson, Corey, Robert A. Lewis, and K. Frank Austen of Harvard showed that biologically generated SRS-A was composed not only of LTC4 but also of leukotriene D4(LTD4) and leukotriene E4(LTE4), which are formed from leukotriene C. Corey’s group also completed a stereo-chemically specific synthesis of all intermediates of the leukotriene pathway, thereby definitively establishing the structures. At that time, synthetic leukotrienes were in such high demand that they were valued at about $1,000 per milligram. Because Corey’s group possessed the world’s supply, they provided leukotrienes to researchers around the world for their leukotriene investigations.
Samuelsson and his mentor Bergstrom, along with John Vane, won the Nobel Prize for Physiology or Medicine in 1982 for their prostaglandin work, and Corey won the Nobel Prize for Chemistry in 1990 for the development of the theory and methodology of organic synthesis.
The leukotrienes exert their effects through G-protein-coupled receptors (GPCRs) that regulate a signal transduction pathway that ultimately causes calcium release from the cells. There are two classes of leukotriene receptors, BVT1 receptors and cysteinyl leukotriene (CysLT) receptors 1 and 2. It is these latter receptors that mediate the actions of the cysteinyl leukotrienes in asthma. One of the first drugs that came out of the leukotriene research was Merck’s montelukast sodium (Singulair), an LTD4 antagonist for treatment of asthma.
Back in 1981, Merck Frosst in Montreal, Canada, hired Anthony W. Ford-Hutchinson from Kings College Hospital Medical School, London, to serve as director of pharmacology. Under Ford-Hutchinson’s leadership, Merck Frosst established biological assays and animal models for modulation of leukotriene receptors in search of a treatment of asthma. In order to find leukotriene receptor antagonists, they hand-screened tens of thousands of compounds from Merck’s compound library at a time when high-through-put (HTS) screening was not yet available. They then decided to use quinolein as their lead compound for their studies on structure-activity relationship (SAR). They arrived at MK-571, which is a thousandfold more potent than quinolein. The clinical trials in 1989 demonstrated that leukotriene receptor antagonists were effective for treating asthma, thereby confirming the pivotal role of leukotrienes in respiratory disease clinically. Unfortunately, MK-571 caused a large increase of liver weight in mice. Merck Frosst scientists discovered that only one enan-tiomer of MK-571 had the liver side effect but that the other, surprisingly, did not. In April 1991 they finally produced montelukast sodium, which possessed desirable attributes such as high intrinsic potency, good oral bioavailability, and long duration of action for a once-daily regimen for asthma. The «mont» in its name is a tribute to the place in which it was discovered, Montreal. In 1998, the FDA approved montelukast sodium for marketing, and Merck sold it under the trademark Singulair, which had annual sales of $2.62 billion in 2004. In the course of 19 years of quest for Singulair, Merck Frosst published more than 800 papers on related topics. The three medicinal chemists who discovered Singulair were Robert N. Young (current vice president of medicinal chemistry), Robert J. Zamboni (past vice president of medicinal chemistry), and Marc Labelle. They were named the 2003 heroes of chemistry by the American Chemical Society.
Anthony Ford-Hutchinson was promoted to executive vice president for worldwide basic research at Merck.
Two additional asthma drugs work via the same mode of action as that of Singulair. They are AstraZeneca’s zaflrlukast (Accolate) and Ono Pharmaceutical’s pranlukast (Onon). These three CysLTj-selective antagonists have become another important class of drugs for managing asthma, as well as allergic rhinitis, another prevalent inflammatory disease.
