Pharmacology of leukotriene receptor antagonists

Aharony D.

Zeneca Pharmaceutical, Wilmington, Delaware.

Preclinical pharmacological studies have demonstrated that cysLT1 receptor antagonists, such as zafirlukast, montelukast, and pobilukast, are potent and selective antagonists of cysteinyl leukotriene (cysLT) activity. In vitro, these agents compete with [3H]LTD4 for binding to cysLT1 receptors present on guinea pig and human lung cell membranes. Both zafirlukast and montelukast have affinities that are approximately two times greater than that of the natural ligand, LTD4. These agents block LTD4- and LTE4-induced contractions of isolated guinea pig trachea, but do not antagonize LTC4-induced contractions, which are putatively mediated by a different LT receptor, cysLT2. The cysLT2 receptor, however, has not yet been found in human airway smooth muscle. In animal models, these drugs inhibit LTD4-, LTE4-, and antigen-induced bronchoconstriction, reduce inflammatory markers in models of pulmonary inflammation, and inhibit antigen-induced late-phase bronchoconstriction. This preclinical profile suggests that cysLT1 receptor antagonists may be useful in treating inflammatory conditions of the respiratory system, such as asthma and allergic rhinitis. Aharony D. Pharmacology of leukotriene receptor antagonists.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=0009620942&dopt=Abstract montelukast, Singulair




Chemistry and structure-activity relationships of leukotriene receptor antagonists

Bernstein PR.

Zeneca Pharmaceuticals, Wilmington, Delaware.

Several strategies have been employed by medicinal chemists in the design of potent and selective leukotriene receptor antagonists-leukotriene structural analogs, FPL 55712 analogs, and random screening of corporate compound banks. Lead compounds were optimized, often through the exchange of ideas with groups working on other chemical series of leukotriene antagonists. Pranlukast can likely be traced to a lead compound identified by random screening that was initially modified by incorporating structural components present in FPL 55712. Montelukast originated from an early quinoline lead, which was modified with leukotriene structural elements. Zafirlukast is based on a lead compound that incorporated structural components from both FPL 55712 and the leukotrienes. Therefore, each medicinal chemistry strategy that was originally employed has successfully identified clinically effective leukotriene receptor antagonists. Bernstein PR. Chemistry and structure-activity relationships of leukotriene receptor antagonists.

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Montelukast for persistent asthma.

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Determination of montelukast sodium in human plasma by column-switching high-performance liquid chromatography with fluorescence detection.

Kamei T.

Drug Metabolism, Development Research Laboratories, Banyu Pharmaceutical Co., Ltd., Saitama, Japan.

MK-0476 (montelukast sodium) is a potent and selective cysteinyl leukotriene receptor antagonist that is being investigated in the treatment of asthma. A simple and sensitive method for the determination of MK-0476 in human plasma was developed using column-switching high-performance liquid chromatography (HPLC) with fluorescence detection. A plasma sample was injected directly onto the HPLC system consisting of a pre-column (Capcell pak MF) and an analytical column (Capcell pak C18) which were connected with a six-port switching valve. The column eluate was monitored with a fluorescence detector (excitation at 350 nm; emission at 400 nm). The calibration curve was linear in a concentration range of 1-500 ng ml(-1) for MK-0476 in human plasma. The intra-day coefficients of variation of all concentrations within the range was less than 9.2%, and the intra-day accuracy values were between 97.2 and 114.6%. This method was used to measure the plasma concentration of MK-0476 following oral administration of the drug in humans.

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In vitro pharmacologic profile of YM158, a new dual antagonist for LTD4 and TXA2 receptors.

Honda K.

Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba-shi, Ibaraki, Japan.

YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl ) propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) antagonizes leukotriene (LT) D4 and thromboxane (TX) A2 receptors. Functional assays in vitro showed that YM158 exhibits competitive dual antagonism of LTD4 and TXA2 receptor-mediated contraction of isolated guinea pig tracheae, with pA2 values of about 8.87 and 8.81, respectively. Its antagonistic activity for the LTD4 receptor was approximately 6.5 times less potent than that of montelukast, and that for the TXA2 receptor was 2.5 times more potent than that of seratrodast. YM158 also inhibited PGD2- and PGF2alpha-induced tracheal contractions. YM158 showed no antagonism against LTC4-, histamine- or carbachol-induced contractions of guinea pig tracheae. Furthermore, YM158 antagonized the stable TXA2 analog U46619-induced aggregation of both guinea pig and human platelets and inhibited the LTD4-induced contraction of guinea pig ileum. From these results, YM158 appears to be a novel, selective dual antagonist for both LTD4 and TXA2 receptors.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9808690&dopt=Abstract montelukast, Singulair