Antiasthmatic Agents Research Articles

The Heck reaction in the production of fine chemicals

An overview is given of the use of the Heck reaction for the production of fine chemicals. Five commercial products have been identified that are produced on a scale in excess of 1 ton/year. The herbicide Prosulfuron(tm)is produced via a Matsuda reaction of 2-sulfonatobenzenediazonium on 3,3,3-trifluoropropene. The sunscreen agent 2-ethylhexyl p-methoxy-cinnamate has been produced on pilot scale using Pd/C as catalyst. Naproxen(tm)is produced via the Heck reaction of 2-bromo-6-methoxy-naphthalene on ethylene, followed by carbonylation of the product. Monomers for coatings are produced via a Heck reaction on 2-bromo-benzocyclobutene. A key step in the production of the antiasthma agent Singulair(tm)is the use of the Heck reaction of methyl 2-iodo-benzoate on allylic alcohol (18) to give ketone (20). The high cost of palladium has spurred much research aimed at the development of more active palladium catalysts. Ligandless catalysts are very attractive for production, but work only on reactive substrates. Palladacycles are much more stable than Pd-phosphine complexes and can be used at higher temperatures. The same effect has been reached with pincer ligands. Bulky ligands lead to coordinatively unsaturated Pd-complexes, which are highly active for the Heck reaction. Recycle of palladium catalysts is also very important to reduce cost. Immobilization of catalysts by attaching ligands to solid support is not very useful, because of leaching and reduced activity. In ligandless Heck reactions the catalyst can be precipitated on carriers such as silica, dicalite, or celite. This material can be restored to its original activity by treatment with I2or Br2.Key words: homogeneous catalysis, palladium, arylation, olefination, ligandless, catalyst recycle.

Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions.

Pharmacokinetic interactions involving anti-infective drugs may be important in the intensive care unit (ICU). Although some interactions involve absorption or distribution, the most clinically relevant interactions during anti-infective treatment involve the elimination phase. Cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 are the major isoforms responsible for oxidative metabolism of drugs. Macrolides (especially troleandomycin and erythromycin versus CYP3A4), fluoroquinolones (especially enoxacin, ciprofloxacin and norfloxacin versus CYP1A2) and azole antifungals (especially fluconazole versus CYP2C9 and CYP2C19, and ketoconazole and itraconazole versus CYP3A4) are all inhibitors of CYP-mediated metabolism and may therefore be responsible for toxicity of other coadministered drugs by decreasing their clearance. On the other hand, rifampicin is a nonspecific inducer of CYP-mediated metabolism (especially of CYP2C9, CYP2C19 and CYP3A4) and may therefore cause therapeutic failure of other coadministered drugs by increasing their clearance. Drugs frequently used in the ICU that are at risk of clinically relevant pharrmacokinetic interactions with anti-infective agents include some benzodiazepines (especially midazolam and triazolam), immunosuppressive agents (cyclosporin, tacrolimus), antiasthmatic agents (theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin, carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine) and anticoagulants (warfarin). Some lipophilic anti-infective agents inhibit (clarithromycin, itraconazole) or induce (rifampicin) the transmembrane transporter P-glycoprotein, which promotes excretion from renal tubular and intestinal cells. This results in a decrease or increase, respectively, in the clearance of P-glycoprotein substrates at the renal level and an increase or decrease, respectively, of their oral bioavailability at the intestinal level. Hydrophilic anti-infective agents are often eliminated unchanged by renal glomerular filtration and tubular secretion, and are therefore involved in competition for excretion. Beta-lactams are known to compete with other drugs for renal tubular secretion mediated by the organic anion transport system, but this is frequently not of major concern, given their wide therapeutic index. However, there is a risk of nephrotoxicity and neurotoxicity with some cephalosporins and carbapenems. Therapeutic failure with these hydrophilic compounds may be due to haemodynamically active coadministered drugs, such as dopamine, dobutamine and furosemide, which increase their renal clearance by means of enhanced cardiac output and/or renal blood flow. Therefore, coadministration of some drugs should be avoided, or at least careful therapeutic drug monitoring should be performed when available. Monitoring may be especially helpful when there is some coexisting pathophysiological condition affecting drug disposition, for example malabsorption or marked instability of the systemic circulation or of renal or hepatic function.

New immunological approaches and cytokine targets in asthma and allergy.

The aims of current asthma treatment are to suppress airway inflammation and control symptoms, and corticosteroids maintain a commanding position in this role. Steroids effectively suppress inflammation in the majority of patients but have little impact on the natural history of this disease. In severe asthmatics, corticosteroids may have relatively less beneficial effects. Recent advances in understanding the inflammatory and immunological mechanisms of asthma have indicated many potential therapeutic avenues that may prevent or reverse abnormalities that underlie asthma. As the roles of effector cells, and of signalling and adhesion molecules are better understood, the opportunities to inhibit or prevent the inflammatory cascade have increased. In addition, there have been advances in the synthesis of proteins, monoclonal antibodies and new small molecule chemical entities, which may provide valuable flexibility in the therapeutic approach to asthma. The novel immunological approaches include the prevention of T-cell activation, attempts to influence the balance of T-helper cell (Th) populations to inhibit or prevent Th2-derived cytokine expression, and the inhibition or blockade of the downstream actions of these cytokines such as effects on immunoglobulin-E and eosinophils. These approaches provide broad as well as highly specific targeting, and also prospects for prevention and reversal of immunological and inflammatory abnormalities associated with asthma. Hopefully, the development of effective antiasthma agents with effects beyond those provided by current therapies coupled with lesser side-effects will further address the unmet needs of asthma.

Recent perspectives in the design of antiasthmatic agents.

Asthma is a common respiratory disorder. It can no longer be viewed as a reversible airway obstruction but should instead be considered primarily as an inflammatory illness that has bronchial hyperreactivity and bronchospasm as its result. There are several potential benefits as well as limitations of the currently available antiasthmatic agents such as anticholinergics, beta 2-selective agonists, methylxanthines, corticosteroids, or mast cell stabilizers. Recent trends in the design of new antiasthmatic agents include isozyme selective phosphodiesterase inhibitors, inhibitors of the biosynthesis of interleukin-4 and IL-4 antagonists, lipoxygenase and leukotriene inhibitors, thromboxane A2 receptor antagonists, potassium channel openers and monoclonal antibodies.

ChemInform Abstract: An Efficient Synthesis of the Antiasthmatic Agent T‐440: A Selective N‐Alkylation of 2‐Pyridone.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Anilide derivatives of an 8-phenylxanthine carboxylic congener are highly potent and selective antagonists at human A(2B) adenosine receptors.

No highly selective antagonists of the A(2B) adenosine receptor (AR) have been reported; however such antagonists have therapeutic potential as antiasthmatic agents. Here we report the synthesis of potent and selective A(2B) receptor antagonists. The structure-activity relationships (SAR) of 8-phenyl-1, 3-di-(n-propyl)xanthine derivatives in binding to recombinant human A(2B) ARs in HEK-293 cells (HEK-A(2B)) and at other AR subtypes were explored. Various amide derivatives of 8-[4-[[carboxymethyl]oxy]phenyl]-1,3-di-(n-propyl)xanthine, 4a, were synthesized. A comparison of aryl, alkyl, and aralkyl amides demonstrated that simple anilides, particularly those substituted in the para-position with electron-withdrawing groups, such as nitro, cyano, and acetyl, bind selectively to human A(2B) receptors in the range of 1-3 nM. The unsubstituted anilide 12 had a K(i) value at A(2B) receptors of 1.48 nM but was only moderately selective versus human A(1)/A(2A) receptors and nonselective versus rat A(1) receptors. Highly potent and selective A(2B) antagonists were a p-aminoacetophenone derivative 20 (K(i) value 1.39 nM) and ap-cyanoanilide 27 (K(i) value 1.97 nM). Compound 27 was 400-, 245-, and 123-fold selective for human A(2B) receptors versus human A(1)/A(2A)/A(3) receptors, respectively, and 8.5- and 310-fold selective versus rat A(1)/A(2A) receptors, respectively. Substitution of the 1,3-dipropyl groups with 1,3-diethyl offered no disadvantage for selectivity, and high affinities at A(2B) receptors were maintained. Substitution of the p-carboxymethyloxy group of 4a and its amides with acrylic acid decreased affinity at A(2B) receptors while increasing affinity at A(1) receptors. 1, 3-Di(cyclohexylmethyl) groups greatly reduced affinity at ARs, although the p-carboxymethyloxy derivative 9 was moderately selective for A(2B) receptors. Several selective A(2B) antagonists inhibited NECA-stimulated calcium mobilization in HEK-A(2B) cells.

An efficient synthesis of the anti-asthmatic agent T-440: a selective N-alkylation of 2-pyridone.

6,7-Diethoxy-1-[1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridin- 4-yl]naphthalene-2,3-dimethanol [T-440, (1)] is a potential anti-asthmatic agent based on selective phosphodiesterase 4 inhibition. It was necessary for the further evaluation of 1 to develop an efficient synthetic route for 1, especially the construction of the 1-(2-methoxyethyl)-2-pyridone moiety. We examined an N-selective alkylation of pyridone derivative (2) in basic media. 2-Methoxyethylation of 2 with 2-methoxyethyl iodide utilizing LiH as the base gave predominantly an N-alkyl pyridone derivative (3a) in 82% yield (N/O-alkylation=92/8), which is compatible with an ab initio calculation of transition-state structures for the methylation of 2-pyridone. Single crystallization of a crude mixture of 3a and 4a furnished pure 3a, which is a key synthetic intermediate of 1.

Pharmacotherapy of asthma in children, with special reference to leukotriene receptor antagonists.

Asthma in adults is generally recognized as a chronic inflammatory airway disease, although this association is less well established in childhood asthma. Thus, recent asthma guidelines have emphasized that asthma treatment should be directed toward the underlying inflammatory aspects of the disease. The prevalence of asthma and resultant hospitalizations and deaths have increased or remained stable over the past 10 years in the United States. In part, this appears to be caused by shortcomings of available antiasthma therapeutic agents. Because these trends are particularly troublesome in children and young adults, there is a need for effective anti-inflammatory therapies that are safe and tolerable. The leukotrienes are a family of lipid mediators that appear to play an important role in the symptomology and pathogenesis of asthma. The results of clinical trials in adults with asthma demonstrated that antileukotriene drugs such as zafirlukast, montelukast, and zileuton improve pulmonary function, decrease asthma symptoms, and decrease the concomitant use of other antiasthma drugs. Most antileukotriene agents are orally bioavailable and well tolerated, offering the potential for improved patient compliance. Montelukast and zafirlukast have received approval for use in pediatric asthma patients, and approval of zafirlukast in this patient population is pending.

Screening methods for antiasthmatic agents

Bronchial asthma is characterized by both bronchoconstriction and airway inflammation which leads to bronchial hyperresponsiveness to various stimuli. Different mediators are implicated in asthma. As the precise etiology is not known and multiple biochemical processes are triggered by different causative factors, it is difficult to have a single drug which can effectively and simultaneously act upon different mediators. This led to an intense search for potent and safe antiasthmatic drugs. This review intends to compile different screening methods for the evaluation of new candidate drugs with potential for the treatment of asthma. These include in vitro, in vivo, receptor binding and enzymatic methods. Detailed experimental methods have been included with appropriate literature citations.

Pyran Template Approach to the Design of Novel A3 Adenosine Receptor Antagonists.

[Table: see text] A3 adenosine receptor antagonists have potential as anti-inflammatory, anti-asthmatic, and anti-ischemic agents. We previously reported the preparation of chemical libraries of 1,4-dihydropyridine (DHP) and pyridine derivatives and identification of members having high affinity at A3 adenosine receptors. These derivatives were synthesized through standard three-component condensation/oxidation reactions, which permitted versatile ring substitution at five positions, i.e., the central ring served as a molecular scaffold for structurally diverse substituents. We extended this template approach from the DHP series to chemically stable pyran derivatives, in which the ring NH is replaced by O and which is similarly derived from a stepwise reaction of three components. Since the orientation of substituent groups may be conformationally similar to the 1,4-DHPs, a direct comparison between the structure activity relationships of key derivatives in binding to adenosine receptors was carried out. Affinity at human A3 receptors expressed in CHO cells was determined vs. binding of [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)-5'-N-methyl-carbamoyladenosine). There was no potency-enhancing effect, as was observed for DHPs, of 4-styryl, 4-phenylethynyl, or 6-phenyl substitutions. The most potent ligands in this group in binding to human A3 receptors were 6-methyl and 6-phenyl analogs, 3a (MRS 1704) and 4a (MRS 1705), respectively, of 3,5-diethyl 2-methyl-4-phenyl-4H-pyran-3,5-dicarboxylate, which had Ki values of 381 and 583 nM, respectively. These two derivatives were selective for human A3 receptors vs. rat brain A1 receptors by 57-fold and 24-fold, respectively. These derivatives were inactive in binding at rat brain A2A receptors, and at recombinant human A2B receptors displayed Ki values of 17.3 and 23.2 μM, respectively. The selectivity, but not affinity, of the pyran derivatives in binding to the A3 receptor subtype was generally enhanced vs. the corresponding DHP derivatives.

NEW INSIGHTS INTO THE MOLECULAR BASIS OF GLUCOCORTICOID ACTION

Because of the realization that inflammation plays a primary role in the pathogenesis of asthma, glucocorticoids are now considered to be the most efficacious antiasthmatic agents. 12 The anti-inflammatory effects of glucocorticoids are mediated through receptors that function by modulating gene expression. Glucocorticoid receptors (GRs) are members of the large steroid/nuclear receptor family that also includes receptors for mineralocorticoids, androgens, estrogens, progesterone, vitamin D, thyroid hormone, and retinoic acid. During the past decade, there has been a tremendous increase in the knowledge of the mechanisms through which glucocorticoids affect gene expression. Much is known about how glucocorticoids enhance activation of gene expression, but an important aspect of the anti-inflammatory effects of glucocorticoids in asthma involves repression of the expression of inflammatory mediators, particularly cytokines. There is less knowledge concerning the mechanisms through which glucocorticoids repress gene expression, but this is an important area of research. Studies have also recently demonstrated a significant role for steroid/nuclear receptor co-activators, histone acetylation, and chromatin structure in gene regulation. This article begins with an overview of glucocorticoid receptors and glucocorticoid-induced gene activation and then focuses on mechanisms of glucocorticoid-mediated gene repression.

Novel, potent, and selective phosphodiesterase-4 inhibitors as antiasthmatic agents: synthesis and biological activities of a series of 1-pyridylnaphthalene derivatives.

The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-2585.HCl) was chosen for further biological evaluation (PDE4 inhibition IC50 = 0.13 nM, selectivity PDE3/4 ratio = 14 000). Compound 3kg showed potent antispasmogenic activities (ED50 = 0.063 mg/kg for reduction of antigen-induced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction of histamine-induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovascular effects. Furthermore, 3kg induced significantly weaker emetic effects than RP73401 after oral administration in ferrets and intravenous administration in dogs (3kg, none of 4 ferrets vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at a dose of 0.3 mg/kg, iv; RP73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited at a dose of 0.3 mg/kg, iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3kg, 2.6 nM; RP73401, 0. 85 nM). This may imply that 3kg has an improved therapeutic ratio because of a broad margin between the Ki value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050).

Effects of the aqueous fraction of the ethanol extract of the leaves of Cissampelos sympodialis Eichl. in human neutrophils.

An aqueous fraction (10-300 micrograms/mL) of the ethanol extract of the leaves of Cissampelos sympodialis Eichl inhibited N-formyl-Met-Leu-Phe (fMLP)-induced release of lysozyme and myeloperoxidase from human neutrophils. Inhibition by the fraction, as well as by dibutyryl-cAMP and prostaglandin E2, was substantially greater when the cells were pretreated with the phosphodiesterase (PDE) inhibitor isobutyl methyl xanthine (IBMX) indicating that the effect may be mediated by cAMP. Measurement of intracellular cAMP levels showed that the fraction (30-100 micrograms/mL) increased the nucleotide levels in IBMX-pretreated neutrophils which was unaffected by propranolol. Cyclic AMP dependent protein kinase A activity was also increased by the fraction (1.5-100 micrograms/mL). Superoxide anion generation induced by fMLP in cytochalasin B-treated cells primed with PAF was not inhibited by the aqueous fraction. The results indicate that the aqueous fraction of Cissampelos sympodialis inhibits neutrophil degranulation by a cAMP-dependent mechanism which may be relevant to the use of the plant as an anti-asthmatic agent in folk medicine.

Effect of DP-1904, a thromboxane synthetase inhibitor, on antigen- and spasmogen-induced bronchoconstriction in rodents

The effect of DP-1904 [6-(1-imidazolylmethyl)-5, 6, 7, 8-tetra-hydronaphthalene-2-carboxylic acid hydrochloride], a selective thromboxane synthetase inhibitor, was examined on antigen- and spasmogen-induced bronchoconstriction in rodents. Oral administration of DP-1904 (1, 3, 10 mg/kg) as well as OKY-046 (sodium ( E)-3[4-(1-imidazolylmethyl)-phenyl]-2-propanoate, 100 mg/kg), significantly inhibited immunoglobulin G-mediated bronchoconstriction in actively sensitized guinea pigs. Immunoglobulin E-mediated bronchoconstriction in actively sensitized rats was also inhibited by both DP-1904 (1, 10 mg/kg) and OKY-046 (100 mg/kg). DP-1904 (3–30 mg/kg) and OKY-046 (30 mg/kg) suppressed leukotriene D 4-induced bronchoconstriction in guinea pigs. In these models, the endogenous levels of thromboxanes significantly increased following the stimulus (antigen and leukotriene D 4). DP-1904 (10 mg/kg) inhibited the increase in thromboxane level in both plasma and bronchial alveolar lavage fluid. These actions of DP-1904 persisted for more than 12 h, indicating a long-lasting effect of DP-1904 on bronchoconstriction. The results showed that the biological activity of DP-1904 in our rodents models is more potent than that of OKY-046 (Ozagrel), which is available as an anti-asthma agent in Japan.

P–660 - Pharmacological profiles of a novel antiasthmatic agent, NIP-520

P–660 - Pharmacological profiles of a novel antiasthmatic agent, NIP-520

Advantage of the use of human liver S9 in the Ames test

The mutagenicity of 13 chemicals was compared using human liver S9 or liver S9 prepared from male Sprague–Dawley rats either non-treated (R-n) or pretreated with phenobarbital/5,6-benzoflavone (R-i). The test compounds used in this study were well recognized procarcinogens requiring cytochrome P450 for metabolic activation. These included polycyclic aromatic hydrocarbons, aromatic amines, heterocyclic aromatic amines, nitrosoamines, and nitropyrene. We used four human liver S9 fractions, one of which was prepared from the liver sample having higher levels of the P450-catalyzed drug metabolizing enzyme activities, a possible explanation for which was enzyme induction by anti-asthma agents for 10 years. The results of the present study are as follows: (1) there were individual differences in the magnitude of the mutagenic activity of the procarcinogens by each S9 fraction used, (2) equivalent mutagenicity of chemicals was seen with three human S9 fractions (H3, H8, and H12), while a human H14 S9 fraction showed higher P450 enzyme activity, leading to much higher mutagenicity than the other three human S9 specimens, (3) the order of magnitude of the mutagenicity of the procarcinogens using human and rat liver S9 fractions was R-i≥H14≥R-n≥H3, H8, and H12, while with 2-aminoanthrathene, N-nitrosodimethylamine, and 1-nitropyrene, this relationship was H3, H8, H12, and H14≥R-n≥R-i. The experimental data in the present study strongly suggest that the complementary use of human liver S9 fraction in the Ames test is a much more useful tool than rat S9 for evaluation of genotoxicity to humans.

Inhibitory effect of ibudilast (KC-404) on the expression of the beta2 integrin family on an eosinophilic cell line (EoL-1).

Adhesion molecules are thought to play a key role in inflammatory processes in bronchial asthma. We previously observed an increased expression of the beta2-integrin family on an eosinophilic cell line (EoL-1) by platelet-activating factor (PAF). In the present study, we examined the effect of ibudilast (KC-404), a novel anti-asthma agent, on beta2 integrin expression induced by PAF. EoL-1 cells (1x10(6)/mL) were incubated in the presence or absence of 10(-6) M ibudilast (KC-404), then cells were cultured in the presence or absence of PAF (10(-7) M) for 45 minutes. Flow cytometric analysis for CD11a, CD11b, and CD18 expression was examined. Ibudilast had an inhibitory effect on beta2 integrin expression induced by PAF [CD11a: 84.8% versus 73.1% (preincubation with ibudilast), CD11b: 35.8% versus 26.2%, CD18 74.9% versus 65.6%]. Ibudilast (KC-404) has anti-inflammatory activities through its inhibitory effect on the expression of adhesion molecules on eosinophils.

Increased use of inhaled corticosteroids and reduced hospitalizations in adult asthmatics: 11 years' experience in a Japanese hospital.

Until recently, inhaled corticosteroids have not been recognized as a first-line drug mainly because of the traditional polypharmaceutical approach to asthma in Japan. To examine the trend more precisely following the introduction of inhaled corticosteroids, we retrospectively analysed the relation between the number of prescriptions for anti-asthma drugs including inhaled corticosteroids and the number of hospitalizations due to asthma exacerbation, near fatal episodes and deaths from asthma for a period of 11 years from 1986 to 1996 at Kobe City General Hospital (KCGH). A marked decline in these actual indices in patients attending KCGH, which shows the improvement in asthma control, started coincidentally with the increased use of inhaled corticosteroid, which was followed by both a discontinuation of the trend for increased use of inhaled beta-agonists and the decreased use of oral anti-asthma agents. There was no significant difference in the mean duration of hospital stays between 1988 and 1996. Although the intensification of patient education is likely to play an important role in enhancing the protective effect of inhaled corticosteroids, we highly suspect that the major contributory factor in the great decline in hospitalizations is the increased use of inhaled corticosteroids.

Synthesis of 3-and 5′-substituted flavone-8-carboxylic acids as ‘three-armed’ leukotriene CysLT 1 receptor antagonists

Molecular modelling of leukotriene CysLT 1 receptor antagonists have suggested that in addition to the two binding sites for a lipophilic and an acidic group, the receptor has a ‘third pocket’ to accommodate ‘three-armed’ ligands such as montelukast 1. Based on the most rigid CysLT 1 receptor antagonist 3'-[2-(2-quinolinyl)ethenyl]flavone-8-carboxylic acid 2, we have synthesised 3-and 5′-substituted flavone derivatives to probe this additional binding pocket. Introduction of large substituents, e.g. 2-quinolinylmethoxy, to the C5′ position of the flavone skeleton abolished the CysLT 1 receptor affinity whereas the same modification at the C3 position yielded a potent CysLT 1 antagonist. This observation implies that the third binding pocket of the receptor has considerable steric tolerance, probably corresponding to the substituents at C3 of the flavone skeleton. Further modification by introducing a C3 substituent containing a basic nitrogen resulted in compound 6g with potent H 1 antihistaminic activity although the CysLT 1 antagonistic activity was much reduced. Further study on the CysLT 1 receptor recognition of three-armed antagonists may facilitate the design of more effective antiasthmatic agents, e.g. dual antagonists of histamine H 1 and leukotriene CysLT 1 receptors.

Structural Requirements for Leukotriene CysLT1 Receptor Ligands

Leukotriene CysLT1 receptor antagonists (also known as LfD4 antagonists) are among the most promising antiasthmatic agents currently under investigation. For the last 20 years there are many thousands of compounds prepared as CysLT1 receptor antagonists and several of them have advanced to the clinical practice. The diverse chemical structures of CysLT1 antagonists pose considerable difficulty in the identification of structural determinants for their activity. This review summarizes the structural modifications within each individual class of compounds and derives the general structural requirements for CysLT1 antagonistic activity. Computer-aided rational design of CysL T1 antagonists have been thoroughly analyzed and a new pharmacophoric model is presented to accommodate almost all SAR data experimentally observed. Since a stable and selective CysLT1 receptor agonist would be a very useful pharmacological tool, especially for the characterization of receptor subtypes, the SARs of CysLT1 agonists have also been discussed in the present paper. These information are also important for the understanding of ligand recognition of the CysLT1 receptor.