- Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast
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The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non-alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti-NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti-asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver-related metabolic diseases.
- Schierle, Simone,Helmst?dter, Moritz,Schmidt, Jurema,Hartmann, Markus,Horz, Maximiliane,Kaiser, Astrid,Weizel, Lilia,Heitel, Pascal,Proschak, Anna,Hernandez-Olmos, Victor,Proschak, Ewgenij,Merk, Daniel
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- Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology
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Multitarget design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist zafirlukast that simultaneously inhibits soluble epoxide hydrolase and activates peroxisome proliferator-activated receptor γ. The triple modulator exhibits robust anti-inflammatory activity in vivo and highlights the therapeutic potential of designed multitarget agents.
- Schierle, Simone,Flauaus, Cathrin,Heitel, Pascal,Willems, Sabine,Schmidt, Jurema,Kaiser, Astrid,Weizel, Lilia,Goebel, Tamara,Kahnt, Astrid S.,Geisslinger, Gerd,Steinhilber, Dieter,Wurglics, Mario,Rovati, G. Enrico,Schmidtko, Achim,Proschak, Ewgenij,Merk, Daniel
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supporting information
p. 5758 - 5764
(2018/06/18)
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- An improved and scalable process for zafirlukast: An asthma drug
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An improved and scalable process for the large-scale production of zafirlukast (Accolate), an important drug for asthma, is discussed along with impurity and scale-up-related issues.
- Goverdhan, Gilla,Reddy, Anumula Raghupathi,Sampath, Aalla,Srinivas, Kurella,Himabindu, Vurimidi,Reddy, Ghanta Mahesh
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experimental part
p. 67 - 72
(2010/04/22)
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- SUBSTITUTED INDOLES
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Disclosed herein are substituted indole cysteinyl leukotriene receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 52-53
(2009/08/14)
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- PROCESSES FOR PREPARING ZAFIRLUKAST
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An improved process for the preparation of substantially pure zafirlukast and pharmaceutical compositions thereof.
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Page/Page column 9
(2009/06/27)
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- Evolution of a series of peptidoleukotriene antagonists: Synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles
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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 arysulfonyl amide group as part of the acidic chain at the C-3 position of the ring. Such compounds had in vitro dissociation constants K(B) in the range 10-9-10-11 M on guinea pig trachea against LTE4 as agonist and inhibition constants (K(i)) ≤ 10-9 M on guinea pig parenchymal membranes against [3H]LTD4. A number of compounds were orally effective at doses ≤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-methyl]benzenesulfonamide, ICI 204,219; pK(B) = 9.67 ± 0.13, K(i) = 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 K(B) ≤ 10-9 M on guinea pig trachea.
- Matassa,Maduskuie Jr.,Shapiro,Hesp,Snyder,Aharony,Krell,Keith
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p. 1781 - 1790
(2007/10/02)
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- Heterocyclic amide derivatives and pharmaceutical use
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The invention concerns novel, pharmaceutically useful, amide derivatives of certain benzoheterocyclylalkanoic acids (and related tetrazoles and acylsulphonamides) of the formula I and salts thereof, wherein the radicals R1, R2, L, X, Y, Z, A1, Q, A2 and M have the meanings set out in the specification. The invention also includes pharmaceutical compositions incorporating a formula I compound or a salt thereof, a process for the manufacture of the said compound, together with intermediates for use in the latter process. STR1
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- Indole and indazole keto sulphones as leukotriene antagonists
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This invention provides a series of novel keto sulfones of formula I STR1 in which the group =A-- is selected from =C(Ra)-- and =N-- and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compound, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processes for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
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