N-[(arylmethoxy)phenyl] carboxylic acids, hydroxamic acids, tetrazoles, and sulfonyl carboxamides. Potent orally active leukotriene D4 antagonists of novel structure

Four series of N-[(arylmethoxy)phenyl] compounds were prepared as leukotriene D4 (LTD4) antagonists. In the hydroxamic acid series, methyl 3-(2-quinolinylmethoxy)benzeneacetohydroxamate (Wy-48,422, 20) was the most potent inhibitor of LTD4-induced bronchoconstriction with an oral ED50 of 7.9 mg/kg. Compound 20 also orally inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ED50 of 3.6 mg/kg. In vitro, against LTD4-induced contraction of isolated guinea pig trachea pretreated with indomethacin and 1-cysteine, 20 produced a pKB value of 6.08. In the sulfonyl carboxamide series, N-[(4-methylphenyl)sulfonyl]-3-(2-quinolinylmethoxy)-benzamide (Wy-49,353, 30) was the most potent antagonist. Compound 30 orally inhibited both LTD4- and ovalbumin-induced bronchoconstriction with ED50s of 0.4 and 20.2 mg/kg, respectively. In vitro, against LTD4-induced contraction of isolated guinea pig trachea, 30 produced a pKB value of 7.78. In the carboxylic acid series, which served as intermediates for the above two series, 3-(2-quinolinylmethoxy)benzeneacetic acid (Wy-46,016, 5) was the most potent inhibitor of LTD4-induced bronchoconstriction (99% at 25 mg/kg, intraduodenally); however, the pKB for this compound was disappointing (5.79). In the tetrazole series, the most potent inhibitor was 2-[[3-(1H-tetrazol-5-ylmethyl)phenoxy]methyl]quinoline (Wy-49,451, 41). The respective inhibitory ED50s were 3.0 mg/kg versus LTD4 and 17.5 mg/kg versus ovalbumin. In the isolated guinea pig trachea, 41 produced a pKB value of 6.70.     

Optimization of the quinoline and substituted benzyl moieties of a series of phenyltetrazole leukotriene D4 receptor antagonists.

This report describes the development of a series of highly potent quinoline-based leukotriene D4 (LTD4) receptor antagonists containing an N-benzyl-substituted phenyltetrazole moiety. They were designed to provide both the correct positioning of the acidic function and secondary lipophilic domain required for strong receptor binding. Members of this series possess high activity in blocking LTD4-induced contractions of isolated guinea pig ileum. Compound 32, LY287192 (2-[[5-[3-[2-(7-chloroquinolin-2- yl)ethenyl]phenyl]-2H-tetrazol-2-yl]methyl]-5-fluorobenzoic acid sodium salt), blocked contraction with a pKB value of 9.1 +/- 0.3. Qualitative structure-activity studies have demonstrated specific requirements for the best activity. In particular, ortho substitution of the benzyl group with an acidic function was crucial for maximum potency. In cases similar to 32, where the benzyl group possesses an ortho carboxylate, the N-2-substituted tetrazole isomer showed 100-fold greater activity relative to the corresponding N-1 isomer. This pattern was reversed when the acid was substituted at the para position. The quinoline unit may be replaced by other nitrogen-containing heterocycles.     

Synthesis of [[(naphthalenylmethoxy)- and [[(quinolinylmethoxy)phenyl]amino]oxoalkanoic acid esters. A novel series of leukotriene D4 antagonists and 5-lipoxygenase inhibitors

A series of novel [[(naphthalenylmethoxy)- and [[(quinolinylmethoxy)phenyl]amino]oxoalkanoic acid esters have been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte (PMN) 5-lipoxygenase (LO) in vitro and as inhibitors of ovalbumin (OA) and leukotriene D4 (LTD4) induced bronchospasm in the guinea pig (GP) in vivo. Many naphthalenyl compounds were potent inhibitors of 5-LO, and several quinolinyl compounds were potent inhibitors of LTD4-mediated bronchospasms in the GP. The most potent naphthalenyl compound, 4-[[3-(2-naphthalenylmethoxy)phenyl]hydroxyamino]-4-oxobutanoic acid, methyl ester (6v), had an IC50 of 0.6 microM in the 5-LO assay. The most potent compound in vivo, 4-[[3-(2-quinolinylmethoxy)phenyl]hydroxyamino]-4-oxobutanoic acid, methyl ester (6e), had ED50's of 3.3 mg/kg and 27.4 mg/kg (intraduodenally) against LTD4- and OA-induced bronchospasm, respectively. When tested as an antagonist of LTD4-induced contraction of isolated GP tracheal spiral strips, 6e was shown to be a competitive inhibitor with a pKB value of 5.33.     

Peptide leukotriene antagonistic activity of AS-35, a new antiallergic drug.

The effects of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (AS-35), a newly synthesized compound, on leukotrienes (LTs) antagonistic activities were investigated in vitro and in vivo. In isolated guinea pig preparations, AS-35 antagonized LTC4-, LTD4- and LTE4-induced contractions of the ileum with IC50 values of 8 nM, 4 nM and 3 nM, respectively. In the trachea, the agent also antagonized LTD4- and LTE4-induced contractions with IC50 values of 10 nM and 20 nM, respectively. However, LTC4-induced tracheal contraction in the presence of L-serine borate was not antagonized by AS-35. Histamine-, acetylcholine-, serotonin- and bradykinin-induced contractions of the ileum, carbachol-, prostaglandin D2-, prostaglandin F2 alpha-induced contractions of the trachea and LTB4-induced chemotaxis of rat polymorphonuclear leukocytes were not inhibited by AS-35. As to the in vivo models, AS-35 (i.v.) dose-dependently antagonized bronchoconstriction induced by i.v.-injection of LTC4 and LTD4 in anesthetized guinea pigs, but did not inhibit histamine-induced bronchoconstriction. Oral administration of AS-35 also antagonized LTD4- as well as antigen-induced LT-mediated bronchoconstriction. In addition, LTD4-induced increase in the cutaneous vascular permeability of guinea pig was inhibited by the drug (p.o.). These results indicate that AS-35 is an orally effective, potent and selective peptide LT antagonist.     

Synthesis and antiallergic activity of a novel series of 5-lipoxygenase inhibitors

A series of novel substituted [[(phenoxymethyl)phenyl]amino]oxoalkanoic acid esters have been synthesized. These compounds were tested in vitro for their ability to inhibit the synthesis of 5-hydroxyeicosatetraenoic acid and leukotriene (LT) B4 from rat polymorphonuclear leukocytes (PMN) and in vivo as inhibitors ovalbumin- (OA) and LTD4-induced bronchospasm in the guinea pig. Compounds 5-12 and 25 had IC50's between 1 and 5.6 microM in the rat PMN 5-lipoxygenase assay. Compounds 1, 3, and 16 inhibited OA-induced bronchoconstriction (61%, 64%, and 57%, respectively), but only 1 showed activity against LTD4-induced bronchoconstriction. When tested against LTD4-induced contraction of isolated guinea pig tracheal spiral strips, 1 was a competitive inhibitor with a pKB of 4.94.     

N-[(arylmethoxy)phenyl] and N-[(arylmethoxy)naphthyl] sulfonamides: potent orally active leukotriene D4 antagonists of novel structure

Two series of compounds, N-[(arylmethoxy)phenyl] sulfonamides and N-[(arylmethoxy)naphthyl] sulfonamides, were prepared as leukotriene D4 (LTD4) antagonists. In the phenyl series, N-[3-(2-quinolinylmethoxy)phenyl]-trifluoromethanesulfonamide (Wy-48,252, 16) was the most potent inhibitor of LTD4-induced bronchoconstriction in the guinea pig. With an intragastric ID50 of 0.1 mg/kg (2-h pretreatment), 16 was 300 times more potent than LY-171,883. Compound 16 also intragastrically inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ID50 of 0.6 mg/kg. In vitro against LTD4-induced contraction of isolated guinea pig trachea pretreated with indomethacin and L-cysteine, 16 produced a pKB value of 7.7. In the rat PMN assay 16 inhibited both 5-lipoxygenase and cyclooxygenase (IC50's = 4.6 and 3.3 microM). In the naphthyl series, N-[7-(2-quinolinylmethoxy)-2-naphthyl]trifluoromethanesulfonamide (Wy-48,090, 47) in addition to potent LTD4 antagonist activity (on isolated guinea pig trachea 47 had a pKB value of 7.04) also had antiinflammatory activity (63% inhibition at 50 mg/kg in the rat carrageenan paw edema assay and 34% inhibition of TPA-induced inflammation at 1 mg/ear in the mouse ear edema model). Perhaps the antiinflammatory activity of 47 was due to its additional activity of inhibiting both 5-lipoxygenase and cyclooxygenase enzymes (IC50's = 0.23 and 11.9 microM, respectively, in rat PMN).     

Synthesis and pharmacological characterization of a series of leukotriene analogues with antagonist and agonist activities

The synthesis and biological characterization of a series of novel leukotriene antagonists and agonists are reported. All of these compounds are derivatives of (5S,6R,7Z)-5-hydroxy-6-mercapto-9-phenyl-7-nonenoic acid. One of the more potent compounds is (5S,6R,7Z)-6-[[(4-carboxy-2-methoxyphenyl)methyl]thio]-5-hydroxy-9 -(4- heptylphenyl)-7-nonenoic acid (3f). In vitro evaluation of this compound on guinea pig trachea revealed that it is a competitive antagonist of LTD4 and LTE4 with pKB values of 6.4 and 5.8, respectively. On guinea pig ileum, the pKB values obtained for it with LTD4 and E4 were both 7.2. The selectivity of 3f was shown by its lack of effect on carbachol, histamine, and barium chloride concentration-response curves in guinea pig trachea.     

The development of a novel series of (quinolin-2-ylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 3. Structural variation of the acidic side chain to give antagonists of enhanced potency

This paper is the third in a series outlining the development of orally active sulfido peptide leukotriene antagonists containing a (quinolin-2-ylmethoxy)phenyl moiety. In this work the systematic variation of the acid side chain substituents led to dramatic and reproducible changes in the oral activity of these compounds, presumably due to alterations in their pharmacokinetic properties. The most potent compound identified, 5-[4-[4-(quinolin-2-yl-methoxy)phenyl]-3-methylbutyl]tetrazole (32), represents a convergence of good in vitro antagonist activity and a 3-10-fold improvement in oral potency over the current clinical candidate 2. The new findings from these optimization studies are as follows: oxygen substitution in the acid side chain was not necessary for antagonist activity, in vitro and in vivo activity was enhanced by alkyl or phenyl substitution on the gamma-carbon of the acid side chain of para-substituted (quinolin-2-ylmethoxy)phenyl derivatives, and free rotation about the side chain carbon atom adjacent to the (quinolin-2-ylmethoxy)phenyl ring was required for activity. The lead compound of this report (32) is a competitive inhibitor of [3H]LTD4 binding to receptor membrane purified from guinea pig lung (Ki = 12 +/- 3 nM) and of the spasmogenic activity of LTC4, LTD4, and LTE4 in guinea pig lung strip. Dosed orally in guinea pigs, this compound blocks LTD4-induced bronchoconstriction (ED50 0.8 mg/kg) and antigen-induced systemic anaphylaxis (ED50 = 1.2 mg/kg).     

Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 1. Initial structure-activity relationships

This series of reports describes the development of orally active, highly potent, specific antagonists of the peptidoleukotrienes containing a (2-quinolinylmethoxy)phenyl moiety. Described in this first report are the structure-activity relationships that led to a more than a 20-fold improvement of the potency and selectivity of the initial chemical lead (RG 5901). From this series of compounds, RG 7152 (16) was identified and selected for further evaluation in the clinic as an antiasthmatic agent. Compound 16 competitively inhibits [3H]LTD4 binding to membranes from guinea pig lung (Ki = 38 +/- 6 nM) and the spasmogenic activity of LTC4, LTD4, and LTE4 in parenchymal lung strips from guinea pigs. Unlike the original lead (RG 5901), compound 16 does not inhibit 5-lipoxygenase from guinea pig PMNs. Following oral administration to guinea pigs, 16 blocks LTD4-induced dermal permeability (ED50 = 6.9 mg/kg), LTD4-induced bronchoconstriction (ED50 = 1.1 mg/kg), antigen-induced bronchoconstriction (ED50 = 2.5 mg/kg), and anaphylactic-induced mortality (ED50 = 16 mg/kg). These studies on structure-activity relationships indicate that there is a requirement for an acidic function and the presence of the (2-quinolinylmethoxy)phenyl moiety in a specific geometric arrangement.     

New potent antagonists of leukotrienes C4 and D4. 1. Synthesis and structure-activity relationships

(p-Amylcinnamoyl)anthranilic acid (3a) had moderate antagonist activities against LTD4-induced smooth muscle contraction on guinea pig ileum and LTC4-induced bronchoconstriction in anesthetized guinea pigs. Modifications were made in the hydrophobic part (cinnamoyl moiety) and the hydrophilic part (anthranilate moiety) of 3a. A series of 8-(benzoylamino)-2-tetrazol-5-yl-1,4-benzodioxans and 8-(benzoylamino)-2-tetrazol-5-yl-4-oxo-4H-1-benzopyrans were revealed to be potent antagonists of leukotrienes C4 and D4. Among both series, ONO-RS-347 (18k) and ONO-RS-411 (19h) were the most potent and orally active antagonists, respectively. Structure-activity relationships are discussed.     

1,3,6-trisubstituted indoles as peptidoleukotriene antagonists: benefits of a second, polar, pyrrole substituent.

1,6-Substituted and 3,5-substituted indoles and indazoles containing acylamino and N-arylsulfonyl amide appendages are potent antagonists of the peptidoleukotrienes LTD4 and LTE4. A compound from the 3,5-substituted indole series, N-[4-[[5-[[(cyclopentyloxy)carbonyl]amino]-1-methylindol- 3-yl]methyl]-3-methoxybenzoyl]-2-methyl-benzenesulfonamide (ICI 204,219), is undergoing clinical evaluation for asthma. Two new elements of structural diversity were introduced to this series of antagonists. An investigation of pyrrole substituents in the 1,6-substituted indoles demonstrated that substitution at C-2 was detrimental to biological activity, but the incorporation of hydrophilic groups at C-3 was beneficial. The introduction of a propionamide moiety at C-3 enhanced activity by 1 order of magnitude; N-[4-[[6-(cyclopentylacetamido)-3-[2-(N- methylcarbamoyl)ethyl]indol-1-yl]methyl]-3-methoxy- benzoyl]benzenesulfonamide (15c) has a pKB of 10.7 at the LTD4 receptor on guinea pig trachea. Modifications of the acylamino portion of the disubstituted antagonists demonstrated that a transposition of the amide CO and NH atoms was viable. N-Cyclopentylmethyl amides in both the 1,6- and 3,5-disubstituted indole series were 1 order of magnitude less potent than the corresponding cyclopentylacetamides. In both series this potency loss could be regained by the incorporation of a propionamide substituent at either C-3 or N-1, respectively. For example, N-[4-[[6-[N-(cyclopentylmethyl)carbamoyl]-3-[2-(pyrrolidin-1 - methylbenzenesulfonamide (39c) has a pKB of 9.5.     

Phenylephrine derivatives as leukotriene D4 antagonists

Two series of phenylephrine derivatives were prepared and tested as inhibitors of leukotriene D4 (LTD4) induced and ovalbumin-induced bronchospasm in the guinea pig. The most potent compound of the urea series, (R)-N,N-diethyl-N-[2-hydroxy-2-[3-(2-quinolinylmethoxy)phenyl]ethyl]-N- methylurea (3, Wy-47,120), was orally active with ED50's of 56 mg/kg vs. LTD4 and 55 mg/kg vs. ovalbumin. When tested as an antagonist of LTD4-induced contraction of isolated guinea pig tracheal strips, 3 was a competitive inhibitor with a p kappa B value of 5.22. In the second series, (R)-3-methyl-5-[3-(2-quinolinylmethoxy)phenyl]-2-oxazolidinone (26, Wy-47,674) had oral ED50's of 36 mg/kg against LTD4 and 95 mg/kg against ovalbumin. Compound 26 selectively antagonized contractile responses of guinea pig trachea evoked by LTD4 (p kappa B = 6.09). In the cat coronary artery, 3 dilated the preparation and blocked the coronary constrictor effect of LTD4. Compound 3 (0.13 mg/kg, iv) also preserved myocardial integrity in rats 48 h after coronary artery ligation. When tested in the rat alcohol-induced gastric lesion model, 3 and 26 manifested a dose-dependent mucosal protection against ethanol.     

Leukotriene receptor antagonists. 2. The [[(tetrazol-5-ylaryl)oxy]methyl]acetophenone derivatives

A series of [[(tetrazol-5-ylaryl)oxy]methyl]acetophenones was synthesized and evaluated as antagonists of leukotriene D4 induced contractions of guinea pig ileum. Substitutions at the 3-position of the acetophenone with ethyl (66), propyl (68), butyl (83), and isobutyl (84) gave -log IC50 values of 7.9, 8.0, 7.8, and 7.7, respectively. Equally potent compounds were obtained when the tetrazol-5-yl group was connected to the second benzene ring in the para position with a chemical bond (67), methylene (68), or ethylene (71). For retention of high antagonist activity, the acetophenone should be substituted in the 2-position by a hydroxyl group and the tetrazole ring should have an acidic hydrogen atom. 1-[2-Hydroxy-3-propyl-4-[[4-(1H-tetrazol-5-ylmethy) phenoxy]methyl]phenyl]ethanone (68, LY1632443) has undergone extensive pharmacologic evaluation for its potential as an antiasthma agent.     

Evolution of a series of peptidoleukotriene antagonists: synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles

1,3,5-Substituted indoles and indazoles have been studied as receptor antagonists of the peptidoleukotrienes. The best of these compounds generally had a methyl group at the N1 position, a [(cyclopentyloxy)carbonyl]amino or 2-cyclopentylacetamido or N'-cyclopentylureido group at the C-5 position, and an arylsulfonyl amide group as part of the acidic chain at the C-3 position of the ring. Such compounds had in vitro dissociation constants (KB) in the range 10(-9) - 10(-11) M on guinea pig trachea against LTE4 as agonist and inhibition constants (Ki) less than or equal to 10(-9) M on guinea pig parenchymal membranes against [3H]LTD4. A number of compounds were orally effective at doses less than or equal to 1 mg/kg in blocking LTD4-induced "dyspnea" in guinea pigs. Compound 45 [N-[4-[[5-[[(cyclopentyloxy)carbonyl]-amino]-1-methylindol-3- yl]methyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide, ICI 204,219; pKB = 9.67 +/- 0.13, Ki = 0.3 +/- 0.03 nM, po ED50 = 0.3 mg/kg] is currently under clinical investigation for asthma. In the indole series, certain alkylsulfonyl amides possessing a 3-cyanobenzyl substituent at the N-1 position (60, 61) were produced that had KB less than or equal to 10(-9) M on guinea pig trachea.     

SKF 104353, a high affinity antagonist for human and guinea pig lung leukotriene D4 receptor, blocked phosphatidylinositol metabolism and thromboxane synthesis induced by leukotriene D4

SKF 104353 (2(S)-hydroxyl-3(R)-carboxyethylthio)-3-[2-(8-phenyloctyl) phenyl] propanoic acid) is a synthetic structural analog of leukotrienes D4 and E4 (LTD4, LTE4). This compound binds to guinea pig and human lung LTD4 receptors with affinities (Ki) of 5 +/- 2 and 10 +/- 3 nM, respectively. The Ki values of a reference compound, FPL 55712, were 2200 and 4500 nM, respectively, approximately 400- and 500-fold less effective than SKF 104353. LTD4- and LTE4-induced biosynthesis of thromboxane B2 has been shown to be mediated by LTD4 receptors in guinea pig lung in vitro. SKF 104353 did not induce synthesis of TxB2 in this system at concentrations of 1-20 microM. When SKF 104353 and increasing concentrations of LTD4 were incubated with guinea pig lung, the dose response curve of LTD4-induced TxB2 biosynthesis was shifted to the right with a -log[KB] = 8.4 +/- 0.2. LTD4-induced phosphatidylinositol (PI) hydrolysis in guinea pig lung has been shown to be the major signal transduction mechanism. In this system, SKF 104353 (1-20 microM) did not promote PI hydrolysis. Pretreatment of the [3H]myo-inositol-labeled guinea pig lung with SKF 104353 shifted the LTD4-induced PI hydrolysis dose response curve to the right, indicating that SKF 104353 inhibited LTD4 receptor-mediated intracellular second messenger formation. These results demonstrate that SKF 104353 is a high affinity, specific LTD4 receptor antagonist. It inhibited LTD4-induced PI hydrolysis and TxB2 biosynthesis in guinea pig lung. SKF 104353 may prove to be an important research tool for research on the activities of leukotrienes and of value therapeutically in the treatment of leukotriene-mediated diseases.     

Leukotriene D4 antagonists and 5-lipoxygenase inhibitors. Synthesis of benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters

A series of novel benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters has been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte 5-lipoxgenase (LO) in vitro and as inhibitors of leukotriene D4 (LTD4) and ovalbumin (OA) induced bronchospasm in the guinea pig (GP) in vivo. In general, inhibitory activity against 5-LO, LTD4, and OA was broadest for benzthiazole-containing analogues (benzthiazole greater than benzimidazole much greater than benzoxazole, benzofuran). The most potent 5-LO inhibitor, 4-[[3-(2-benzthiazolylmethoxy)-phenyl]hydroxyamino]-4-oxobutanoic acid methyl ester (7), had an IC50 of 0.36 microM. Compound 7, however, was inactive vs. OA. The most potent compound in vivo, 4-[[3-[(1-methyl-2-benzimidazolyl)methoxy]phenyl]-amino] -4-oxobutanoic acid methyl ester 4, inhibited both LTD4- and OA-induced bronchospasm by 83% and 60%, respectively, at 50 mg/kg intraduodenally. Compound 4 was studied in the Ames assay employing five strains of bacteria (TA1535, TA1537, TA1538, TA98, and TA100) with and without S-9 rat liver enzyme metabolic activation, and there was no significant number of reversions noted.     

Leukotriene (LT) receptor antagonists. Heterocycle-linked tetrazoles and carboxylic acids. LY203647

LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl] ethanone, is an orally active antagonist of LTD4- and LTE4-induced responses in a variety of test systems. We prepared a new series of LT antagonists based on a proposed model of LY171883 binding to the LTE4 receptor in which the n-propyl and tetrazole moieties of LY171883 occupy those parts of the receptor to which the C1-C5 chain and the cysteinyl carboxyl of LTE4 bind, respectively. The new compounds have an acidic function corresponding to the glycine carboxyl of LTD4 linked through a heterocyclic group which is proposed to bind to the LTD4 receptor where the cysteinyl glycine amide bond of LTD4 binds. LY203647, 1-[2-hydroxy-3-propyl-4-[4-[2-[4-(1H-tetrazol-5-yl)butyl]-2H- tetrazol-5-yl]butoxy]phenyl] ethanone, showed good LTD4 antagonist activity with a suitable pharmacologic and toxicologic profile and has been chosen for clinical evaluation.     

In vitro antagonism of ONO-1078, a newly developed anti-asthma agent, against peptide leukotrienes in isolated guinea pig tissues.

We evaluated the antagonist activity of ONO-1078 against peptide leukotrienes (LTs) by a radioligand binding assay and functional experiments in guinea pigs. In the radioligand binding assay, ONO-1078 inhibited [3H]LTD4 and [3H]LTE4 bindings to lung membranes (Ki = 0.99 and 0.63 nM, respectively) and was 2,000- to 3,000-fold more potent than FPL55712. Antagonism of ONO-1078 against [3H]LTC4 binding (Ki = 5640 nM) was approximately twofold more potent than that of FPL55712. The antagonism of ONO-1078 against [3H]LTD4 binding was competitive. In functional experiments, ONO-1078 showed competitive antagonism against the LTC4- and LTD4-induced contractions of guinea pig trachea and lung parenchymal strips with a pA2 range of 7.70 to 10.71 and was approximately 400- to 3,300-fold more potent than FPL55712. Interestingly, in the presence of an inhibitor of the bioconversion of LTC4 to LTD4, ONO-1078 also antagonized the LTC4-induced contraction of guinea pig trachea (pA2 = 7.78). ONO-1078 significantly reversed the LTD4-induced prolonged contraction without effect on the KCl- and BaCl2-induced contractions of guinea pig trachea. Furthermore, ONO-1078 antagonized the antigen-induced SRS-A mediated contraction of guinea pig trachea. On the other hand, ONO-1078 showed no antagonism against histamine, acetylcholine, 5-hydroxytryptamine, prostaglandin D2 and U-46619. In addition, ONO-1078 showed little or no effect on the activities of cyclooxygenase, 5-lipoxygenase and thromboxane synthetase. These in vitro studies indicate that ONO-1078 is a highly potent, selective and competitive antagonist of peptide leukotrienes that acts with higher affinity at LTD4 and LTE4 receptors than LTC4 receptors.     

Quinones. 4. Novel eicosanoid antagonists: synthesis and pharmacological evaluation

A new series of omega-phenyl-omega-quinonylalkanoic acids and related compounds was synthesized. The compounds were tested for their inhibitory effects on U-44069-induced contraction of the rabbit aorta. (+/- )-7-(3,5,6-Trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (4d) (AA-2414) with pA2 value of 8.28 was one of the most potent compounds. Compound 4d inhibited U-46619-induced contraction of the guinea pig lung (pA2 = 8.29) and U-44069-induced aggregation of the guinea pig platelet (IC50 = 3.5 x 10(-7) M). Compound 4d displaced the binding of [3H]U-46619 to guinea pig platelets (IC50 = 7.4 x 10(-9) M). Compound 4d also showed very potent inhibitory effects with an MED of 0.3 mg/kg (po) on U-46619-, LTD4-, PAF-, or IgG1-induced bronchoconstriction in guinea pigs. The enantiomers of 4d were prepared. The R-(+) isomer 8a was active in both in vitro and in vivo tests, but the S-(-) isomer 8b was much less active. We concluded that the antiasthmatic effects of 4d were based mainly on the TXA2 receptor antagonistic action. In addition, compound 4d showed potent inhibitory effects on PGD2-, PGF2 alpha-, and 11-epi-PGF2 alpha-induced contraction of the guinea pig tracheal strips. The diverse inhibitory effects might be expressed in terms of eicosanoid-antagonistic activity.     

Calcium modulators of the anellated dihydropyridine type. Synthesis and pharmacologic action

The anellated dihydropyridines 4a-l can be gained by Hantzsch-like synthesis from 5,5-dimethylcyclohexanedione (1), the aromatic aldehydes 2a-l and methyl-beta-aminocrotonate (3). Cyclisation of the side chains with bromosuccinimide or pyridiniumbromideperbromide leads to the octahydrofuro[3,4-b]chinoline-diones 4m-p. Structures of type 4 are characterized by the spectroscopic data. Positive inotropic effects, caused by calcium agonism, are exerted by the tested substances at the isolated, electrically stimulated left guinea pig atrium, 4j being the most potent with an intrinsic activity of 0.79, compared with ethyl 4-[2-(difluoromethoxy)phenyl]-1, 4,5,7-tetrahydro-2-methyl-5-oxo-furo[3,4-b]pyridine-3-carboxylate. BaCl2-induced contractions at the guinea pig ileum are suppressed dose-dependently.