Paul Masson

The synthesis of a leukotriene with SRS-like activity

Abstract The synthesis and biological characteristics of an SRS-like leukotriene are described.

Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enxyme induction

Abstract Structure-activity studies leading to the discovery of 1 (MK-0476) are described. The initial compound of this series, 2, was a potent leukotriene D4 (LTD4) antagonist, but was also a peroxisomal enzyme inducer in the mouse. Structure-activity relationships around the thioether chain were explored to remove this undesirable feature. It was found that alkyl substituents in the s position relative to the carboxylic acid reduce the potency as a peroxisomal enzyme inducer while preserving the LTD4 antagonistic properties. Dialkyl substitution essentially eliminates the enzyme induction. The optimal styryl quinoline 1 exhibited high in vitro potency and in vivo activity on oral dosing without significant liver enzyme induction in the mouse.

Differing mechanisms for leukotriene D4-induced bronchoconstriction in guinea pigs following intravenous and aerosol administration

Leukotriene D4 (LTD4) when administered intravenously or by aerosol to guinea pigs produced changes in pulmonary mechanics including a decrease in dynamic compliance and an increase in pulmonary resistance. The effects of intravenous LTD4 (0.5 microgram kg-1) were short lived and abolished by pretreatment of the animal with either cyclooxygenase inhibitors, a thromboxane synthetase inhibitor (OKY 1555) or an SRS-A antagonist (FPL 55712). These findings suggest that bronchoconstriction produced by the intravenous infusion of LTD4 at 0.5 microgram kg-1 is due to the release of thromboxane A2. However, in animals treated with indomethacin, LTD4 at higher doses (greater than 0.8 microgram kg-1) still elicited a bronchoconstriction which could be blocked by FPL 55712. Nebulization of 0.1 - 1.0 microgram of LTD4 into the lung produced prolonged changes in pulmonary mechanics which were inhibited by FPL 55712 and were potentiated by indomethacin. LTD4, therefore, when administered by aerosol produced effects on the lung which were not mediated by cyclooxygenase products. Responses to nebulized rather than intravenous LTD4 in the guinea pig may more closely resemble those seen in human tissues.

Biological activity of leukotriene sulfones on respiratory tissues.

The biological activity of synthetic leukotriene C4, D4 and E4 sulfone has been determined in respiratory smooth muscle in vitro and in vivo. The sulfones of LTC4, LTD4 and LTE4 were potent contractile agonists on indomethacin-treated guinea pig tracheal chains with respective pD2-values of 8.2, 8.0 and 7.9. Contractions were submaximal (75–85% of the cholinergic maximum), slow in onset, prolonged in duration, slowly reversed by washing (compared to acetylcholine or histamine) and were partially reversed by 2μM FPL-55712. The sulfones of LTC4, LTD4 and LTD4 also contracted indomethacin-treated guinea pig parenchyma (respective pD2′s of 7.9 8.2 and 7.8) and rat parenchyma (respective pD2′s of 7.1, 7.2 and 7.2) but were inactive on rat trachea (0.01–2.0 gmM). When administered intravenously to anaesthetized guinea pigs, the sulfones of LTD4, LTE4 and to a lesser degree LTC4 (respective ED50′s - 0.5; 2.0 and 4.6 μg/kg) elicited dose-dependent increases in inflation pressure which were antagonized by FPL-55712 and indomethacin. Leukotriene C4, D4 and E4 sulfones display a qualitatively similar profile of biological activity to that of their corresponding sulfides.

Discovery of L-791,943: A potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor

Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-alpha = 0.67 microM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey.

The activity of synthetic leukotriene C-1 on guinea pig trachea and ileum

The effects of synthetic leukotriene C-1 (LTC-1) on isolated guinea pig trachea and ileum have been determined and compared to histamine. LTC-1 produced a slow contraction of the trachea and the ileum with pD2 values of 8.7 +/- 0.1 (n = 14) and 8.5 +/- 0.1 (n = 13), respectively. In comparison, the pD2 values for histamine were 5.6 +/- 0.1 (n = 6) and 6.2 +/- 0.1 (n = 6), indicating LTC-1 was 2-3 orders of magnitude more potent. LTC-1 was antagonised by FPL 55712 with pA2 values of 6.9 +/- 0.1 (n = 5) and 6.4 +/- 0.1 (n = 7) on the trachea and ileum, respectively. Incubation with lipoxidase produced a time and enzyme dependent loss of biological activity and a concurrent shift in U.V. absorption spectrum.

The discovery of a new structural class of potent orally active leukotriene D4 antagonists

Abstract A new, potent, orally active leukotriene D 4 receptor antagonist has been discovered. The structure -activity relationship leading to L-695,499 is described.

Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters

A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.

Comparative study of the pulmonary effects of intravenous leukotrienes and other bronchoconstrictors in anaesthetized guinea pig

Pulmonary responses to intravenous leukotrienes C4, D4 and E4 administered as a bolus injection and by continuous infusion were studied in anesthetized guinea pigs. LTD4, LTC4 and LTE4 (respective ED50 of 0.21 +/- .1, 0.64 +/- .2 and 2.0 +/- .1 microgram kg-1) produced dose-dependent increases in insufflation pressure when given as a bolus injection to anesthetized guinea pigs (Konzett-Rössler). Bronchoconstriction was antagonized by FPL-55712 (50-200 micrograms kg-1), and indomethacin (50-200 micrograms kg-1) but was not significantly altered by mepyramine (1.0 mg kg-1), methysergide (0.1 mg kg-1), intal (10 mg kg-1) mepacrine (5 mg kg-1) or dexamethasone (10 mg kg-1). The beta adrenoceptor blocker, timolol (5 micrograms kg-1) produced a significantly greater potentiation of the responses to the leukotrienes than to arachidonic acid, histamine and acetylcholine. Responses to bolus injection of LTE4 but not LTD4 or LTC4 were partially antagonized by atropine (100 micrograms kg-1) and bilateral vagotomy. In experiments of a different design, continuous infusion of LTD4 and LTE4 (2.8-3.2 micrograms kg-1 min-1) into indomethacin-treated animals produced slowly developing increases in pulmonary resistance and decreases in compliance. The increase in resistance produced by LTE4 and LTD4 was partly reversed by intravenous FPL-55712 (1.0 mg kg-1) and atropine (100 micrograms kg-1) but was almost completely reversed by FPL-55712 (3 - 10 mg kg-1). These findings indicate that leukotrienes can produce bronchoconstriction in guinea pigs through cyclooxygenase-dependent and cyclooxygenase independent mechanisms both of which are blocked by FPL-55712. Cholinergic mechanisms are involved in the mediation of part of the response to bolus injection of LTE4 as well as a small part of the initial response to continuous infusion of LTD4 and LTE4. Intrinsic beta adrenoceptor activation serves to down modulate responses to the leukotrienes to a greater extent than responses to arachidonic acid, histamine and acetylcholine.

Substituted 2-pyridinemethanol derivatives as potent and selective phosphodiesterase-4 inhibitors

The synthesis and the phosphodiesterase-4 (PDE4) inhibitory activity of 2-pyridinemethanol derivatives is described. The evaluation of the structure-activity relationship (SAR) in this series of novel PDE4 inhibitors led to the identification of compound 9 which exhibits excellent in vitro activity, desirable pharmacokinetic parameters and good efficacy in animal models of bronchoconstriction.