Yves Girard

Quinolines as potent 5-lipoxygenase inhibitors: Synthesis and biological profile of L-746,530

Leukotriene biosynthesis inhibitors have potential as new therapeutic agents for asthma and inflammatory diseases. A series of novel substituted 2-cyanoquinolines have been synthesized and the structure activity relationships were evaluated with respect to their ability to inhibit the formation of leukotrienes via the 5-lipoxygenase enzyme. [1S,5R]-2-Cyano-4-(3-furyl)-7-¿3-fluoro-5-[3-(3 alpha-hydroxy-6,8-dioxabicyclo[3.2.1]-octanyl)]phenoxymethyl ¿quinoline (L-746,530) 3 represents a distinct class of inhibitors and possesses in vitro and in vivo potency comparable or superior to naphthalenic analog (L-739,010) 2.

Urinary leukotriene E4 levels during early and late asthmatic responses

The sulphidopeptide leukotrienes C4 and D4 (LTC4, LTD4) are potent bronchoconstrictor mediators, released from human lung fragments after challenge with specific allergens in vitro. The purpose of this study was to measure urinary LTE4 (metabolite of LTC4 and LTD4) in subjects undergoing inhalation challenges with allergens or occupational sensitizing agents in the laboratory. Eighteen subjects with previously documented isolated early asthmatic responses (EARs), isolated late asthmatic responses (LARs), or dual (both early and late) asthmatic responses were studied. Urinary LTE4 levels increased in subjects who developed either isolated EARs (mean fall in FEV1, 27.98%) or early responses preceding LARs (mean fall in FEV1, 15.01%). The baseline levels of LTE4 were 150.26 (SEM, 49.5) pg/mg of creatinine in the isolated responders and 66.60 (SEM, 13.5) pg/mg of creatinine in the dual responders. These levels increased to 1816 (SEM, 606.1) pg/mg of creatinine (p = 0.041) and 174.80 (SEM, 40.1) pg/mg of creatinine (p = 0.025), respectively, after the EAR. The degree of maximal bronchoconstriction during the EAR correlated with the levels of LTE4 (r = 0.68; p = 0.001). No significant increase in urinary LTE4 levels occurred during the LAR. These results suggest that the LTE4 precursors, LTC4 and LTD4, are important bronchoconstrictor mediators causing EARs after allergen inhalation.

2-Pyridinyl-3-(4-methylsulfonyl)phenylpyridines: Selective and orally active cyclooxygenase-2 inhibitors

A series of novel 2-pyridinyl-3-(4-methylsulfonyl)phenylpyridines has been synthesized and evaluated with respect to their ability to inhibit the isozymes of cyclooxygenase, COX-1, and COX-2. Optimum COX-2 activity is observed by introduction of a substituent at C5 of the central pyridine. 5- Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine 33 was identified as the optimum compound in this series.

The synthesis of a leukotriene with SRS-like activity

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

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.

Slow reacting substance of anaphylaxis, SRS-A: Assignment of the stereochemistry

We have recently described the structure elucidation of slow reacting substance of anaphylaxis S(SRS-A) from lung and of a slow reacting substance (SRS) from basophilic leukaemia cells as 5-hydroxy-6-cysteinylglycinyl-7,9,11,14-eicosatetraenoic acid. The stereochemistry of this molecule has now been shown to be 5(S)-hydroxy- 6(R)-cysteinylghlycinyl-7,9-trans-11,14-ciseicosatetraenoic acid by comparison of the synthetic and natural products and their derivatives using mass spectrometric and HPLC chromatographic techniques. The synthetic and natural compounds are also indistinguishable by their pharmacological properties, their conversion by soybean lipoxygenase, and their UV spectra.

Studies on L‐640,035: a novel antagonist of contractile prostanoids in the lung

1 The effects of L‐640,035 (3‐hydroxymethyl‐dibenzo [b,f] thiepin‐5,5‐dioxide) have been studied on pulmonary smooth muscle contraction in vitro and in vivo. 2 When studied in vitro on guinea‐pig tracheal chains, L‐640,035 produced significant shifts in the dose‐response curves to a prostaglandin (PG) endoperoxide analogue (U‐44069) (pA2 7.0), PGF2α (pA2 5.9) and PGD2 (pA2 6.5). L‐640,035 produced no significant shift in the dose‐response curves to leukotriene D4 or histamine and produced a small but statistically significant shift in the dose‐response curve to 5‐hydroxytryptamine (5‐HT) (pA2 5.2). With the exception of PGF2α, Schild analysis did not in general indicate competitive inhibition. The main metabolite of L‐640,035, L‐636,499, also produced significant parallel shifts in the dose‐response curves to U‐44069 (pA2 6.0) and PGF2α (pA2 6.0), but with some reduction in the maximal contraction. 3 When L‐640,035 was administered intravenously to guinea‐pigs, significant inhibition of increases in pulmonary resistance or insufflation pressure induced by U‐44069 (ED50 0.16 mg kg−1), leukotriene D4 (ED50 0.25 mg kg−1) and 5‐HT (ED50 3.4 mg kg−1) but not histamine (ED50> 10 mg kg−1) was observed. 4 When L‐640,035 was administered intravenously to dogs a significant inhibition of increases in pulmonary resistance induced by U‐44069 (ED50 0.85 mg kg−1) but not histamine (ED50> 30 mg kg−1) was observed. 5 When L‐640,035 was administered by the intraduodenal route to dogs at doses of 3 and 10 mg kg−1 significant inhibition of increases in pulmonary resistance induced by sodium arachidonate (3 mg kg−1 i.v.) was observed with a duration of action of > 255 min. 6 It is concluded that L‐640,035 is a novel, relatively selective, and orally active antagonist of the actions of contractile prostanoids on pulmonary smooth muscle.

Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment

The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.