Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene D4 receptor antagonists. 4. Addition of chromone moiety enhances leukotriene D4 receptor binding affinity.

The combination of the benzopyran-4-one ring, a moiety found in the prototype leukotriene antagonist, FPL 55,712, with the (2-quinolinylmethoxy)phenyl group led to a significant increase in leukotriene receptor binding affinity. This modification resulted in a 10,000-fold improvement in binding affinity compared to FPL 55,712. Compound 7 (RG 12553), with a Ki value of 0.1 nM, has higher affinity than the natural agonist LTD4 and is one of the most potent LTD4 antagonists reported. The structure-activity relationships of this series of potent leukotriene antagonists are discussed.

Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene D4 receptor antagonists. 2. Effects of an additional phenyl ring on receptor affinity.

This series of reports describe the development of orally active, highly potent, specific antagonists of the peptidoleukotrienes containing a (2-quinolinylmethoxy)phenyl moiety. The compounds reported in this paper contain an additional phenyl ring, which has significantly improved the receptor affinity. The effect of changes in the linkage between the two phenyl rings as well as the orientation of the acidic functional group on biological activity are discussed. Many of these compounds have high affinity to the sulfidopeptide leukotriene D4 receptors with Ki values ranging between 2 and 20 nM and are orally active. Compound 27 [RG 12525, 5-[[2-[[4-(2-quinolinylmethoxy)phenoxy]- methyl]phenyl]methyl]-1H-tetrazole] represents the best combination of in vitro and in vivo biological activity in this series and has been selected for further evaluation in clinical studies of asthma.

The inhibition of 5-lipoxygenase by RG 6866.

The generation of leukotrienes C4, D4 and E4 from arachidonic acid is dependent upon the activity of 5-lipoxygenase (5-LOX). The effects of RG 6866 (N-methyl-4-benzyloxyphenylacetohydroxamic acid) on the activity of guinea pig 5-LOX in vitro and in vivo were determined in the present study. The generation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) from arachidonic acid by isolated guinea pig peritoneal polymorphonuclear (PMN) cells was inhibited by incubation with RG 6866 (IC50 = 0.20 microM). A similar effect (IC50 = 0.23 microM) was observed when 5-HETE production was measured in a supernatant fraction from PMNs. Additionally, the compound did not inhibit 3H-LTD4 binding to guinea pig membranes. In actively sensitized guinea pigs pretreated with indomethacin, propranolol and pyrilamine, RG 6866 inhibited antigen-induced systemic anaphylaxis and LTD4-dependent bronchoconstriction in a dose-dependent manner following oral administration. In the pulmonary anaphylaxis model, significant (p less than 0.05) inhibition of the mortality was observed within 30 min and maintained through four hours after treatment with RG 6866 (50 mg/kg i.g.). Finally, orally administered RG 6866 inhibited the formation of LTC4 in these animals with an ED50 = 24.0 mg/kg. These findings indicate that RG 6866 is an inhibitor of 5-LOX both in vitro and in vivo.

The effect of RG 12525 on leukotriene D4-mediated pulmonary responses in guinea pigs.

RG 12525 (5-(2-[4-quinolin-2-yl)methoxyl] phenoxymethyl)benzyl tetrazole) is under investigation as a specific inhibitor of leukotriene D4 (LTD4). The present studies examine the effect of orally administered RG 12525 on LTD4 mediated pulmonary responses in three separate guinea pig models. The compound inhibited antigen-induced mortality in the systemic anaphylaxis model with an ED50 (95% confidence interval) = 2.2 (0.8-6.4) mg/kg. In this model, the activity half-life of RG 12525 was shown to be 6.5 hours and the compound offered significant protection within 15 minutes of administration. RG 12525 also protected against LTD4-induced bronchoconstriction in a model measuring changes in pulmonary function with an ED50 = 0.6 (0.4-1.0) mg/kg. The same level of activity was observed in a similar model which monitored changes in pulmonary function in response to exogenous antigen in actively-sensitized guinea pigs. Together, these data indicate that RG 12525 is a potent, orally active LTD4 antagonist which possesses the requisite profile for potential clinical development.

Antagonism of peptidoleukotrienes and inhibition of systemic anaphylaxis by RG 12525 in guinea pigs.

RG 12525 was determined to be a specific, competitive and orally effective antagonist of the peptidoleukotrienes, LTC4, LTD4 and LTE4, in several assays utilizing guinea pigs. In vitro, RG 12525 competitively inhibited 3H-LTD4 binding to lung membranes (Ki = 3.0 +/- 0.3 nM) and competitively antagonized the spasmogenic activity of LTC4, LTD4 and LTE4 on lung strips (KB values = 3 nM) with greater than 8000 fold selectivity. In vivo, RG 12525 orally inhibited LTD4 induced wheal formation (ED50 = 5 mg/kg with a t1/2 = 10 hrs at 9 mg/kg), LTD4 induced bronchoconstriction (ED50 = 0.6 mg/kg), and anaphylactic death (ED50 = 2.2 mg/kg with a t1/2 = 7 hrs at 10 mg/kg) and antigen induced bronchoconstriction (ED50 = 0.6 mg/kg). RG 12525 represents a significant improvement in receptor affinity and oral efficacy and thus, is a valuable pharmacological tool to evaluate peptidoleukotrienes in allergic diseases.

Cardiopulmonary effects of celiprolol and bisoprolol in serotonin-infused cats.

The effects of celiprolol and bisoprolol on cardiopulmonary function in serotonin-infused cats were compared. Celiprolol reversed the bronchoconstrictive effect of serotonin at doses greater than or equal to 1.0 mg/kg. Also, decreases in mean arterial pressure and heart rate were noted after administration of 3-10 and 10 mg/kg celiprolol, respectively. In contrast, bisoprolol tended to induce bronchoconstriction. Reductions in mean arterial pressure and heart rate were observed with 1 or 3 mg/kg. Bisoprolol administration at 10 mg/kg was lethal. The unique ability of celiprolol to induce bronchodilation enhances its therapeutic potential.

The effect of calcium antagonists on allergic pulmonary distress in actively sensitized rats.

The induction of allergic pulmonary distress (APD) in ovalbumin sensitive rats can be used as a model of human allergic asthma. In this model, control animals exhibit a rapid decrease in minute volume (Vm) when challenged with ovalbumin (OA) by aerosol (3% solution). The present study compared the effects of pretreatment with calcium antagonists on the induction of APD. By the aerosol route of administration, 5 min before OA, verapamil HCl (6% solution) significantly (P less than 0.05) dampened the allergic response during all 12 min monitored. At an equivalent concentration, diltiazem HCl significantly (P less than 0.05) inhibited the response during 6 of 12 min, whereas nifedipine failed to significantly (P greater than 0.05) alter the response to OA. Verapamil and nifedipine proved to be equally effective in a dose-dependent manner against OA-induced APD, however, when administered orally (-60 min, 5, 10 or 20 mg/kg). At doses of 10 mg/kg and higher, both calcium antagonists consistently inhibited (P less than 0.05) the response. Diltiazem was inactive when administered orally at a dose as high as 20 mg/kg. The present data suggest that the calcium antagonists verapamil, nifedipine and diltiazem, can attenuate APD and therefore might be clinically active agents in the treatment of allergic asthma.

Relationship between progesterone suppression and pregnancy in rats.

Four luteolytic agents were administered to groups of pregnant rats to examine the quantitative relationship between serum progesterone levels and the maintenance of pregnancy. Each agent inhibited progesterone in a dose-dependent manner, however only three, azastene, thiosemicarbazone and dihydrotestosterone, adversely affected pregnancy. A statistical analysis of the data suggests that, regardless of the mechanism of action of a particular luteolytic agent, a treatment-induced depression of serum progesterone to concentrations less than 45% of that of the controls on day 11 of pregnancy is incompatible with pregnancy maintenance.

Antagonism of the in vivo and in vitro effects of leukotriene D4 by SC-39070 in guinea pigs.

Leukotriene D4 (LTD4) causes contractions of guinea pig isolated ilea, evokes pulmonary bronchoconstriction and induces lesions of the dermal vasculature. In the present study, we assessed the antagonism of these actions by SC-39070 compared to FPL-55712, a known LTD4 receptor antagonist. In guinea pig isolated ileum preparations, SC-39070 displayed selective antagonism of LTD4 with a pA2 = 8.20 +/- 0.06 (S.E.) and a Schild plot slope of -1.20. Administered intravenously to artificially-respired guinea pigs one minute prior to the agonist, SC-39070 antagonized (p less than 0.05) the bronchoconstrictive effect of LTD4 in a dose-dependent manner (0.5-10 mg/kg). At a dose of 2.0 mg/kg, i.v. this activity was retained through a 60 minute pretreatment interval. Similarly, after oral administration of SC-39070, there was a dose-dependent antagonism of the bronchoconstrictive activity of LTD4 (MED50 = 3.8 mg/kg). Antagonism of LTD4-induced bronchoconstriction was evidenced after oral administration of SC-39070 within one hour of treatment and efficacy was retained as long as 20 hours after treatment at a dose of 10 mg/kg. Finally, intravenously administered SC-39070 blocked LTD4-induced dermal permeability in guinea pigs with a minimum effective dose of 1.0 mg/kg. In each assay, the LTD4 antagonism evidenced after treatment with SC-39070 appeared to be equal to or greater than that observed after treatment with FPL-55712.