119515-00-3Relevant academic research and scientific papers
QUINOLINE COMPOUNDS AS SELECTIVE AND/OR DUAL MODULATORS OF BILE ACID RECEPTORS AND LEUKOTRIENE CYSTEINYL RECEPTORS
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, (2022/02/15)
The present invention relates to compounds of formula (I), their pharmaceutical compositions and uses, in particular for the treatment and/or prevention of diseases mediated by bile acid receptors, FXR and GPBAR1, and cysteinyl leukotriene receptors (CysLTR).
Structural Basis for Developing Multitarget Compounds Acting on Cysteinyl Leukotriene Receptor 1 and G-Protein-Coupled Bile Acid Receptor 1
Fiorillo, Bianca,Sepe, Valentina,Conflitti, Paolo,Roselli, Rosalinda,Biagioli, Michele,Marchianò, Silvia,De Luca, Pasquale,Baronissi, Giuliana,Rapacciuolo, Pasquale,Cassiano, Chiara,Catalanotti, Bruno,Zampella, Angela,Limongelli, Vittorio,Fiorucci, Stefano
, p. 16512 - 16529 (2021/11/24)
G-protein-coupled receptors (GPCRs) are the molecular target of 40% of marketed drugs and the most investigated structures to develop novel therapeutics. Different members of the GPCRs superfamily can modulate the same cellular process acting on diverse pathways, thus representing an attractive opportunity to achieve multitarget drugs with synergic pharmacological effects. Here, we present a series of compounds with dual activity toward cysteinyl leukotriene receptor 1 (CysLT1R) and G-protein-coupled bile acid receptor 1 (GPBAR1). They are derivatives of REV5901-the first reported dual compound-with therapeutic potential in the treatment of colitis and other inflammatory processes. We report the binding mode of the most active compounds in the two GPCRs, revealing unprecedented structural basis for future drug design studies, including the presence of a polar group opportunely spaced from an aromatic ring in the ligand to interact with Arg792.60 of CysLT1R and achieve dual activity.
CYANOMETHYLPYRIDINE DERIVATIVES
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, (2008/06/13)
The present invention relates to new cyanomethylpyridine dervatives of formula I wherein Y represents N or CH;R1 represents hydrogen, fluoro, chloro, difluoro or dichloro; R2 represents hydrogen or C1-4alkyl;n is 0 or 1; p is 0 or 1; A represents a covalent bond or a group of formula -CONHC-H(Ar)-, -NHCH(Ar)-, -S02NHCH(Ar)-,NHCONHCH(Ar) or OCONHCH(Ar),and when p is 1,A can also represent CH(Ar)NH; and AT represents phenyl or phenyl substituted with halogen,C M alkyl, C1-4 alkoxy or trifluoromethyl. These compounds are PAF antagonist and/or 5-lipoxygenase inhibitors.
SUBSTITUTED QUINOLINYL AND NAPHTHALENYLBENZAMIDES OR BENZYLAMINES AND RELATED COMPOUNDS USEFUL AS ANALGESICS
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, (2008/06/13)
This invention relates to novel quinolinyl-and naphthalenylbenzamides or benylamines and related disclosed compounds of the formula STR1 wherein X is nitrogen, NO or CR 1 ; Y is C(R 1)(R 2)O, OC(R. sup.1)(R 2), C(R 1)(R 2)N(R 3), N(R. sup.3)C(R 1)(R. sup.2) or C(R 1)=C(R 2); wherein R 1, R 2, and R 3 are independently hydrogen or lower alkyl containing 1 to 10 carbon atoms; Z is oxygen or (R 1)(R 2); R 4 is R 1, benzyl, benzyl ring substituted with R 5, benzyl alpha monosubstituted with R. sup.1, benzyl ring substituted with R 5 and alpha monosubstituted with R 1, phenyl, phenylalkyl containing 2 to 10 carbon atoms in the alkyl group or phenylalkyl ring substituted with R. sup.5 and containing 2 to 10 carbon atoms in the alkyl group; wherein R. sup.5 is R 1, lower alkoxy containing 1 to 10 carbon atoms, halogen, trihalomethyl, NO 2, N(R 1)(R 2) or C(O)N(R 1)(R 2); R 6 is R 1 or R. sup.6 is C(O)(R 7) with the proviso that Z is not oxygen; and wherein R 7 is R 1, phenyl, perfluoroalkyl containing 1 to 10 carbon atoms, phenylalkyl containing 1 to 10 carbon atoms in the alkyl group; or a pharmaceutically acceptable acid addition salt thereof, and their use in the treatment of pain mediated by the biological peptide, bradykinin. In particular, the preferred compounds are where X is nitrogen, and Y is CH 2 O of the above structure.
N- Carboxylic Acids, Hydroxamic Acids, Tetrazoles, and Sulfonyl Carboxamides. Potent Orally Active Leukotriene D4 Antagonists of Novel Structure
Musser, John H.,Kreft, Anthony F.,Bender, Reinhold H. W.,Kubrak, Dennis M.,Grimes, David,et al.
, p. 240 - 245 (2007/10/02)
Four series of N- compounds were prepared as leukotriene D4 (LTD4) antagonists.In the hydroxamic acid series, methyl 3-(2-quinolinylmethoxy)benzeneacetohydroxamate (Wy-48,422, 20) was the most potent inhibitor of LTD4-induced bronchoconstriction with an oral ED50 of 7.9 mg/kg.Compound 20 was also orally inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ED50 of 3.6 mg/kg.In vitro, against LTD4-induced contraction of isolated guinea pig trachea pretreated with indomethacin and 1-cysteine, 20 produced a pKB value of 6.08.In the sulfonyl carboxamide series, N--3-(2-quinolinylmethoxy)-benzamide (Wy-49,353, 30) was the most potent antagonist.Compound 30 orally inhibited both LTD4- and ovalbumin-induced bronchoconstriction with ED50s of 0.4 and 20.2 mg/kg, respectively.In vitro, against LTD4-induced contraction of isolated guinea pig trachea, 30 produced a pKB value of 7.78.In the carboxylic acid series, which served as intermediates for the above two series, 3-(2-quinolinylmethoxy)benzeneacetic acid (Wy-46,016, 5) was the most potent inhibitor of LTD4-induced bronchoconstriction (99percent at 25 mg/kg, intraduodenally); however, the pKB for this compound was disappointing (5.79).In the tetrazole series, the most potent inhibitor was 2-methyl>quinoline (Wy-49,451, 41).The respective inhibitory ED50s were 3.0 mg/kg versus LTD4 and 17.5 mg/kg versus ovalbumin.In the isolated guinea pig trachea, 41 produced a pKB value of 6.70.
