107753-66-2Relevant articles and documents
Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology
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
, p. 5758 - 5764 (2018/06/18)
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.
Evolution of a series of peptidoleukotriene antagonists: Synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles
Matassa,Maduskuie Jr.,Shapiro,Hesp,Snyder,Aharony,Krell,Keith
, p. 1781 - 1790 (2007/10/02)
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.
Heterocyclic amide derivatives and pharmaceutical use
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, (2008/06/13)
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
