- Design, synthesis and biological evaluation of benzo[1.3.2]dithiazolium ylide 1,1-dioxide derivatives as potential dual cyclooxygenase-2/5-lipoxygenase inhibitors
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3-(4-Bromophenyl)-6-nitrobenzo[1.3.2]dithiazolium ylide 1,1-dioxide (5) was discovered as a new prototype for dual inhibitors of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). Thus, the structure-activity relationships of benzo[1.3.2]dithiazolium ylide 1,1-dioxide skeleton were carried out. The 6-NO2 group played an essential role in the inhibitory activity. In addition, moderate-sized lipophilic substituents at the para-position of the 3-aryl moiety were required for dual COX-2/5-LOX inhibitory activity. Among the identified potent dual inhibitors, 3-(4-tbutylphenyl) derivative 30c (IC50 values of 0.27 μM and 0.30 μM against COX-2 and 5-LOX, respectively) and 3-(4-biphenyl) derivative 30f (IC50 values of 0.50 μMand 0.15 μMagainst COX-2 and 5-LOX, respectively) were the most potent dual COX-2/ 5-LOX inhibitors. Intraperitoneal administration of 30c at 100 mg/kg demonstrated potent acute antiinflammatory activity. As a result, benzo[1.3.2]dithiazolium ylide 1,1-dioxide represented a novel scaffold for the exploitation in developing dual COX-2/5-LOX inhibitors.
- Tan, Chen-Ming,Chen, Grace Shiahuy,Chen, Chien-Shu,Chang, Pei-Teh,Chern, Ji-Wang
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experimental part
p. 6316 - 6328
(2011/12/02)
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- TRICYCLIC INHIBITORS OF 5-LIPOXYGENASE
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Described herein are compounds and pharmaceutical compositions containing such compounds, which inhibit the activity of 5-lipoxygenase (5-LO). Also described herein are methods of using such 5-LO inhibitors, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions, diseases, or disorders.
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Page/Page column 85
(2010/11/28)
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- New COX-2/5-LOX inhibitors: Apoptosis-inducing agents potentially useful in prostate cancer chemotherapy
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The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs) have been found to be implicated in a variety of cancers, including prostate cancer. To develop new therapeutic treatments, it therefore seemed interesting to design dual COX-2/5-LOX inhibitors. We report here the synthesis and in vitro pharmacological properties of diarylpyrazole derivatives that have in their structure key pharmacophoric elements to obtain optimal interaction with subsites of active pockets in both enzyme systems. Using a molecular modeling approach, a set of SAR data is proposed, highlighting the importance of the sulfonyl group of one of the aryl moieties in terms of proliferation inhibition and/or apoptosis induction.
- Pommery, Nicole,Taverne, Thierry,Telliez, Aurélie,Goossens, Laurence,Charlier, Caroline,Pommery, Jean,Goossens, Jean-Fran?ois,Houssin, Raymond,Durant, Fran?ois,Hénichart, Jean-Pierre
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p. 6195 - 6206
(2007/10/03)
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- Synthesis and activity of a new methoxytetrahydropyran derivative as dual cyclooxygenase-2/5-lipoxygenase inhibitor
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Dual COX-2/5-LO inhibitors are described as potential new therapeutic agents for inflammatory diseases. A surprisingly potent effect of a 5-LO pharmacophoric group on the COX-2 inhibition is presented as well as pharmacological in vitro and in vivo results.
- Barbey, Sabine,Goossens, Laurence,Taverne, Thierry,Cornet, Josephine,Choesmel, Valerie,Rouaud, Celine,Gimeno, Gilles,Yannic-Arnoult, Sylvie,Michaux, Catherine,Charlier, Caroline,Houssin, Raymond,Henichart, Jean-Pierre
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p. 779 - 782
(2007/10/03)
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- Imidazole lipoxygenase inhibitors
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Certain novel imidazole derivatives having the ability to inhibit the lipoxygenase enzyme and having formula (I), wherein Y is hydrogen, C1 -C8 alkyl, halosubstituted C1 -C4 alkyl, phenyl, substituted phenyl, C7 -C14 phenylalkyl, C7 -C14 (substituted phenyl)alkyl, pyridyl, substituted pyridyl, C6 -C13 pyridylalkyl or C6 -C13 (substituted pyridyl)alkyl, wherein each substituent is independently halo, nitro, cyano, C1 -C4 alkyl, C1 -C4 alkoxy, halosubstituted C1 -C4 alkyl, halosubstituted C1 -C4 alkoxy, NR4 R5, CO2 R4 or CONR4 R5, wherein R4 and R5 are each, independently, hydrogen or C1 -C6 alkyl; Ar1 and Ar2 are each, independently, phenylene, mono-substituted phenylene or di-substituted phenylene, wherein the substituents are, independently, halo, C1 -C4 alkyl, C1 -C4 alkoxy, halo-substituted C1 -C4 alkyl or halo-substituted C1 -C4 alkoxy; X and X1 are each, independently, O, S, SO or SO2 ; R' is hydrogen or C1 -C4 alkyl; and R2 and R3 are each, independently, methylene, ethylene or propylene. These compounds are useful for the treatment of disease states such as bronchial asthma, skin disorders and arthritis in mammals, and as the active ingredient in pharmaceutical compositions for treating such conditions.
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- PYRAN DERIVATIVES AND THEIR USE AS INHIBITORS OF 5-LIPOXYGENASE
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The invention concerns a cyclic ether derivative of the formula I, wherein Ar1 is optionally substituted phenyl, naphthyl or a 9-or 10-membered bicyclic heterocyclic moiety; A1 is a direct link to X1 or (l-3C)alkylene; X1 is oxy, thio, sulphinyl, sulphony
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- BICYCLIC HETEROCYCLIC DERIVATIVES AS 5-LIPOXYGENASE INHIBITORS
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The invention concerns a bicyclic heterocyclic derivative of the formula I wherein Q is an optionally substituted 9-membered bicyclic heterocyclic moiety containing 1 or 2 N's and optionally a further N, O or S heteroatom; A1 is a direct link to X1 or (1-3C)alkylene; X1 is oxy, thio, sulphinyl, sulphonyl or imino; Ar is optionally substituted phenylene or pyridylene; R1 is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and R2 and R3 together form a group of the formula ?A2?X2?A3? which, together with the carbon atom to which A2 and A3 are attached, defines a ring having 5 to 7 ring atoms, wherein each of A2 and A3 is (1-3C)alkylene and X2 is oxy, thio, sulphinyl or sulphonyl; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase
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- BENZOXAZINE DERIVATIVES AS INHIBITORS OF LEUKOTRIENES
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The invention concerns a bicyclic heterocyclic compound of the formula I wherein Q is an optionally substituted 10-membered bicyclic heterocyclic moiety containing 1 or 2 N's and a further O or S heteroatom; A1 is a direct link to X1 or (1-3C)alkylene; X1 is oxy, thio, sulphinyl, sulphonyl or imino; Ar is optionally substituted phenylene or pyridylene; R1 is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and R2 and R3 together form a group of the formula -A2-X2-A3- which, together with the carbon atom to which A2 and A3 are attached, defines a ring having 5 to 7 ring atoms, wherein each of A2 and A3 is (1-3C)alkylene and X2 is oxy, thio, sulphinyl or sulphonyl; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase
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- Thioxo quinoline compounds, composition and method of use
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The invention concerns a thioxo heterocycle of the formula I STR1 wherein Q is a 10-membered bicyclic heterocyclic moiety containing 1 or 2 N's which bears 1 or 2 thioxo substituents and which is optionally further substituted; A1 is a direct l
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- SULPHONAMIDE DERIVATIVES
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The invention concerns sulphonamide derivatives of the formula I wherein R1 includes (1-4C)alkyl; R2 and R3 together form ?A2 ?X2 ?A3? which defines a ring having 5 to 7 ring atoms, wherein A2 and A3 each is (1-3 C)alkylene and X2 is oxy, thio, sulphinyl or sulphonyl; A1 is a direct link to X1 or is (1-3 C)alkylene; X1 is oxy, thio, sulphinyl, sulphonyl or imino; Ar is optionally substituted phenylene or Ar is pyridylene; Q is nitrogen or of the formula CR7, wherein R7 includes hydrogen, halogeno, (1-4 C)alkyl and (1-4 C)alkoxy; each of R4 and R5 is (1-4 C)alkyl, (3-4 C)alkenyl, (3-4 C)alkynyl or optionally substituted phenyl, benzyl or pyridyl, or R5 may be hydrogen; and R6 has any of the meanings defined for R7; or a pharmaceutically-acceptable salt thereof; processes for their manufacture; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors
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- Methoxytetrahydropyrans. A new series of selective and orally potent 5- lipoxygenase inhibitors
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Investigation of the SAR of the lead (methoxyalkyl)thiazole 1-[3-(naphth- 2-ylmethoxy)phenyl]-1-thiazol-2-ylpropyl methyl ether (1, ICI 211965) led to the methoxytetrahydropyrans, a new series of 5-lipoxygenase (5-LPO) inhibitors exemplified by the parent compound 4-[3-(naphth-2- ylmethoxy)phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (4f). In vitro 4f inhibited leukotriene C4 (LTC4) synthesis in zymosan-stimulated plasma-free mouse macrophages and LTB4 synthesis in A-23187-stimulated human whole blood (IC50s 0.5 nM and 0.07 μM, respectively). In the rat 4f inhibited LTB4 synthesis in blood ex vivo and in zymosan-inflamed air pouch exudate with an ED50 3 h after oral dosing of 10 mg/kg in each system. In seeking more potent orally active compounds, strategies were explored in congeners of 4f for reducing lipophilicity without sacrificing potency. For example, replacement of 2-naphthyl of 4f by various aza- and oxoheterocycles afforded compounds in which log P is reduced by 1.7-2.3 units while potency in human whole blood in vitro was maintained or enhanced relative to 4f. In addition, the oxoheterocyclic replacements provided compounds with improved oral potency and the preferred compound from this group is 6-[[3-fluoro-5-(4- methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]methyl]-1-methylquinol-2-one (4y). In the in vitro systems, 4y inhibited LT formation with IC50s in mouse macrophages and human whole blood of 3 nM and 0.02 μM, respectively. 4y did not inhibit the synthesis of cyclooxygenase (CO) products at concentrations up to 500 μM in human blood, a selectivity for 5-LPO over CO of >20 000-fold. In the rat 4y inhibited the formation of LTB4 in blood ex vivo and in inflammatory exudate with ED50s 3 h after oral dosing of 0.9 and 0.3 mg/kg, respectively. 4y was more potent in vitro in human whole blood and in rat blood ex vivo at 3 h than either the 5-LPO inhibitor A-64077 or the FLAP antagonist MK-886. Based on these data 4y (ICI D2138) has been entered into development as an orally active, selective 5-LPO inhibitor for clinical evaluation in inflammatory conditions in which LTs are believed to play a role.
- Crawley,Dowell,Edwards,Foster,McMillan,Walker,Waterson
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p. 2600 - 2609
(2007/10/02)
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- HETEROCYCLES FOR USE AS INHIBITORS OF LEUKOTRIENES
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The invention concerns a heterocycle of the formula I wherein Q is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; A is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene or cyclo(3-6C)alkylene; X is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents or Ar is an optionally substituted 6-membered heterocyclene moiety containing up to three nitrogen atoms; R 1 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; and R 2 and R 3 together form a group of the formula --A 2 --X 2 --A 3 -- which, together with the carbon atom to which A 2 and A 3 are attached, defines a ring having 4 to 7 ring atoms, wherein A 2 and A 3, which may be the same or different, each is (1-4C)alkylene and X 2 is oxy, thio, sulphinyl, sulphonyl or imino; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.
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