- Structural Basis for Developing Multitarget Compounds Acting on Cysteinyl Leukotriene Receptor 1 and G-Protein-Coupled Bile Acid Receptor 1
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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.
- 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
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p. 16512 - 16529
(2021/11/24)
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- ARYL- AND HETEROARYLAMID DERIVATIVES AS PDE10A ENZYME INHIBITOR
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The invention relates to compounds of the formula and their use as pharmaceutical ingredients, in particular for the treatment of CNS related diseases (PDE 10A inhibitors).
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Page/Page column 25
(2012/01/14)
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- Radiosynthesis and in vivo evaluation of [11C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain
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2-((4-(1-[11C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy) methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC50 = 0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [11C]CH3I, ~45% yield, >92% radiochemical purity, >370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [11C]MP-10 had highest brain accumulation in the PDE10A enriched-striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [11C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood-brain-barrier may limit the clinical utility of [11C]MP-10 as a PDE10A PET tracer.
- Tu, Zhude,Fan, Jinda,Li, Shihong,Jones, Lynne A.,Cui, Jinquan,Padakanti, Prashanth K.,Xu, Jinbin,Zeng, Dexing,Shoghi, Kooresh I.,Perlmutter, Joel S.,MacH, Robert H.
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p. 1666 - 1673
(2011/04/16)
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- BICYCLIC HETEROARYL COMPOUNDS AS PDE10 INHIBITORS
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The invention pertains to tricyclic heteraaryi compounds that serve as effective phosphodiesterase (PDE) inhibitors. The invention also relates to compounds which are selective inhibitors of PDE 10. The invention further relates to pharmaceutical compositions comprising such compounds; and the use of such compounds in methods for treating certain central nervous system (CNS) or other disorders. The invention relates also to methods for treating neurodegenerative and psychiatric disorders, for example psychosis and disorders comprising deficient cognition as a symptom.
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Page/Page column 20-21
(2009/07/18)
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- Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3- yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia
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By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.
- Verhoest, Patrick R.,Chapin, Douglas S.,Corman, Michael,Fonseca, Kari,Harms, John F.,Hou, Xinjun,Marr, Eric S.,Menniti, Frank S.,Nelson, Frederick,O'Connor, Rebecca,Pandit, Jayvardhan,Proulx-LaFrance, Caroline,Schmidt, Anne W.,Schmidt, Christopher J.,Suiciak, Judith A.,Liras, Spiros
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experimental part
p. 5188 - 5196
(2010/03/01)
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- Heteroaromatic quinoline compounds
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The invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors. In particular, the invention relates to said compounds which are selective inhibitors of PDE10. The invention also relates to intermediates for preparation of said compounds; pharmaceutical compositions comprising said compounds; and the use of said compounds in a method for treating certain central nervous system (CNS) or other disorders.
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Page/Page column 23-24
(2008/06/13)
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- PHOSPHODIESTERASE 10 INHIBITION AS TREATMENT FOR OBESITY-RELATED AND METABOLIC SYNDROME-RELATED CONDITIONS
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The present invention provides methods to decrease body weight and/or body fat in animals, e.g., in the treatment of overweight or obese patients (e.g., humans or companion animals), or as a means to produce leaner meat in food stock animals (e.g., cattle, chickens, pigs), methods to treat non-insulin dependent diabetes (NIDDM), metabolic syndrome, or glucose intolerance, in patients in need thereof by administering a PDE10 inhibitor (alone or in combination with another therapeutic agent), kits for the above-identified therapeutic uses, and methods of identifying PDE10 inhibitors for the above-described therapeutic uses.
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- CYANOMETHYLPYRIDINE DERIVATIVES
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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.
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- SUBSTITUTED QUINOLINYL AND NAPHTHALENYLBENZAMIDES OR BENZYLAMINES AND RELATED COMPOUNDS USEFUL AS ANALGESICS
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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.
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- QUINOLINYL-BENZOPYRAN DERIVATIVES AS ANTAGONISTS OF LEUKOTRIENE D4
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This invention relates to certain quinolinyl-benzopyran compounds and their use as valuable pharmaceutical agents, particularly as lipoxygenase inhibitors and/or leukotriene antagonists and/or mediator release inhibitors possessing anti-inflammatory and anti-allergic properties.
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- QUINOLINYL-BENZOHETEROBICYCLIC DERIVATIVES AS ANTAGONISTS OF LEUKOTRIENE D4
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This invention relates to certain quinolinyl-benzoheterobicyclic compounds and their use as valuable pharmaceutical agents, particularly as lipoxygenase inhibitors and/or leukotriene antagonists and/or as mediator release inhibitors useful as anti-inflamm
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- N- Carboxylic Acids, Hydroxamic Acids, Tetrazoles, and Sulfonyl Carboxamides. Potent Orally Active Leukotriene D4 Antagonists of Novel Structure
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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.
- Musser, John H.,Kreft, Anthony F.,Bender, Reinhold H. W.,Kubrak, Dennis M.,Grimes, David,et al.
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p. 240 - 245
(2007/10/02)
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- QUINOLINYL-CHROMONE DERIVATIVES AND USE FOR TREATMENT OF HYPERSENSITIVE AILMENTS
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This invention relates to certain quinolinyl-chromone compounds and their use as valuable pharmaceutical agents, particularly as lipoxygenase inhibitors and/or leukotriene antagonists possessing anti-inflammatory and anti-allergic properties.
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