Leukotriene antagonist

The fatty acid-like leukotrienes derived from the addition of glutathione to products of the lipoxygenase branch of the arachidonic cascade are closely associated with manifestations of asthma. Many compounds designed to antagonize leukotrienes at the receptor level incorporate long alkyl chains to mimic the leukotrienes backbone in addition to the sulfur-containing moieties that stand in for glutathione. The reaction 

The structure of the leukotrienes receptor antagonist cinalukast (58-9) bears only the vaguest resemblance to its predecessor, or, for that matter, to a leukotriene. Reaction of the cyanomethylphosphonate (58-1) with hydrogen sulfide converts the nitrile to a thioamide (58-2). Treatment of that intermediate with the bromoketone 

The antiasthamtic activity of the sulfur-free substituted long chain fatty acid seratrodast (59-5) is attributed to the antagonism of thromboxanes, whose structures also include a fatty side chain, rather than to leukotrienes. Friedel-Crafts acylation of benzene with the acid chloride from monomethyl pimelate (59-1) leads to 

Oxidation of the aldehyde group in mixed ether (60-2) by means of perchlorate affords the corresponding carboxylic acid. That product is then converted to its acid chloride (60-6) with thionyl chloride. Treatment of this last intermediate with the substituted pyridine (60-7) leads to the corresponding amide and thus pidamilast (60-8) [62]. 

A relatively simple benzamide inhibitor of phosphodiesterase 4 has proven to be useful for treating chronic pulmonary obstmctive disease (COPD). The synthesis 

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Oxo-4//-pyrido[],2-n]pyrimidin-2-yl]oxymethylsaccharin derivatives 418 exhibited human leukocyta elastase inhibitory activities (94EUP626378, 95USP5378720). 2-Substituted 4//-pyrido[l, 2-n]pyrimidin-4-one (419) is a potent human leukocyta elastase inhibitors (A", 1.79/xM) (96USP5512576). The 4//-pyrido[l,2-n]pyrimidin-4-one moiety was included in leukotriene antagonist 2-ethynylthiazole derivatives (98JAP(K) 98/195063)... 

Salmon, J.A. and Garland, G. (1991). Leukotriene antagonists and inhibitors of leukotriene biosynthesis as potential therapeutic agents. Prog. Drug Res. 37, 9-73. 

Findlay, S.R., Barden, J.M., Easley, C.B. and Glass, M. (1992). Effect of the oral leukotriene antagonist ICI 204,219 on the antgen-induced bronchoconstriction in subjects with asthma. J. Allergy Clin. Immunol. 89, 1040-1045. 

For example, (Ipc)2BCl was found to be an advantageous in the enantioselective reduction in the large-scale preparation of L-699,392, a specific leukotriene antagonist of interest in the treatment of asthma.147... 

Patients receiving these agents may notice improvement in 1 to 2 weeks, but maximal benefit may not be seen for 4 to 6 weeks. Cromolyn and nedocromil appear to be similar in efficacy to the leukotriene antagonists and theophylline for persistent asthma.18 Both agents are well tolerated with adverse effects limited to cough and wheezing. Bad taste and headache have also been reported with nedocromil. One dose of cromolyn or nedocromil prior to exercise or allergen exposure will provide effective prophylaxis for 1 to 2 hours. Cromolyn and nedocromil are not as effective as albuterol for prophylaxis of exercise-induced asthma. 

Holgate ST, Bradding P, Sampson AP. Leukotriene antagonists and synthesis inhibitors new directions in asthma therapy. J Allergy Clin Immunol 1996 98 1-13. 

Antiasthmatics Bronchodilators Anti-inflammatories Leukotriene antagonists... 

Although leukotriene antagonists represent a new therapeutic alternative, published studies to date have shown them to be no more effective than peripherally selective antihistamines and less effective than intranasal corticosteroids. However, combined use with antihistamines is more effective than antihistamine treatment alone. 

Sustained-release theophylline is less effective than inhaled corticosteroids and no more effective than oral sustained-release /J2-agonists, cromolyn, or leukotriene antagonists. 

Anderson, W., et al., "A Single Nucleotide Polymorphism in the 5-Lipoxygenase Gene is Associated with a Reduced Response to Leukotriene Antagonists," Am. Rev. Respir. Crit. Care Med., 163(5), A198 (2000). 

Currie GP, Lima JJ, Sylvester JE, Lee DK, Cockburn WJ, Lipworth BJ. (2003) Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma. Br J Clin Pharmacol. 56, 422-426. 

Leukotriene antagonist Tetrazolyl-aromatic thioethers 89EUP298583... 

Leukotriene antagonist Tetrazolyl-2-quinolinyl methoxy aryl ethers 90JMC1186... 

There is no role for other anti-inflammatory drugs such as sodium cromoglycate, nedocromil, keto-tifen, leukotriene antagonists or antihistamines in COPD. 

Table 3.4 Measured and calculated log P values (Clog P) of leukotriene antagonists ...

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