Anti-asthmatic activity

Despite extensive investigation, the precise mechanism of action of cromolyn in man is still u nown, but it is generally accepted that this agent exerts much of its anti-asthmatic activity by inhibiting the release of mediators from sensitised mast cells (10). It is perhaps pertinent to reflect on how this aspect of the drug s mode of action was first discovered. Cromolyn... 

A synthetic route to optically active eprozinol, an anti-asthmatic compound, has been developed by efficient enantioselective hydrogenations of a- and /farriino ketone hydrochloride derivatives with a MCCPM-rhodium catalyst [30]. 

Inhibits degranulation of mast cells also inhibits release of histamine and SRS-A (a leukotriene) from the mast cell. This inhibits the early asthmatic response by stabilizing the mast cell also inhibits the late asthmatic response. It has no intrinsic bronchodilator, antihistaminic, anticholinergic, vasoconstrictor, or anti-inflammatory activity. 

At that time we considered our stock data on anti-asthmatic compounds from experimental asthma studies in humans. Thus, we knew that mono- and bischromones were highly active by inhalation, but that none of the compounds which we had prepared up to that time were orally effective. This lack of oral activity was, we decided, due to the high polarity and low lipophilic character of the chromone derivatives that we had prepared up to that time. For example, cromolyn had a pKa of about 1.5 and an octanol/water (pH 7.4 aqueous buffer) log D value of about -3.5. Such a compound would be expected to have a very poor absorption profile. This was reflected in its short plasma half-life following intravenous administration and the fact that its plasma levels following oral administration in a number of species were extremely low ( ). 

It was time for our first major re-think. Basically we had shown that our general medicinal chemistry approach to oral activity had been successful. These more lipophilic chromones were indeed being absorbed from the gastro-intestinal tract and reaching their required site of action, but we concluded that one could not use the rat PCA test, or indeed any of our newly developed tests, in a quantitatively predictive sense, for the identification of compounds which would be active anti-asthmatic agents, of the cromolyn type, in humans. I suspect that others have more recently come to the same conclusion about the PCA test, following the clinical evaluation of their own selected compounds. 

Fisons. Ironically this company was founded on fertilizer manufacture and for many years this was a strength of the company. However, losses resulted in the whole fertilizer division being sold to Norsk-Hydro in 1982. This helped profits for the company to rise from 9.3 million in 1981 to 21.1 million in 1982. Its major interests are pharmaceuticals—where its most important success has been the anti-asthmatic drug Intal—and agrochemicals. Diversification into making scientific apparatus and laboratory chemicals, and horticultural materials like composts and peat, were tried, but in the 1990s these were sold to leave the company to concentrate on pharmaceuticals. In 1995 two thirds of its pharmaceutical R D activities were sold to Astra Pharmaceuticals. 

N. Burrib, J. Vantikommua, J. Chem. Pharm. Res. 2012, 4, 3991-4000. Synthesis, anti-bacterial, anti-asthmatic and antidiabetic activities of novel 3-substituted quinazolin-4-ones using l-butyl-3-methyl-imidazohumtetrafluoro borate [bmim+] [BF -] as a green, efficient and reusable catalyst under solvent free conditions. 

In 2007, Birman et al. showed that BTM (23) could also be used as a powerful desymmetrization agent [53]. Indeed, by subjecting lobelanidine to 20mol% of 23 in the presence of propionic acid anhydride (1.1 equiv.) in CHCI3 at room temperature, the corresponding propionic ester was obtained in quasi-enantiopure form and up to 92% yield. Jones oxidation and subsequent hydrolysis eventually resulted in the isolation of (-)-lobeline, a natural product exhibiting anti-asthmatic, expectorant, and respiratory stimulant activities (Scheme 41.6). 

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