- QUINOLINE COMPOUNDS AS SELECTIVE AND/OR DUAL MODULATORS OF BILE ACID RECEPTORS AND LEUKOTRIENE CYSTEINYL RECEPTORS
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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).
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Page/Page column 44-45
(2022/02/15)
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- 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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- Selective Aromatic C-H Hydroxylation Enabled by η6-Coordination to Iridium(III)
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We report an aromatic C-H hydroxylation protocol in which the arene is activated through η6-coordination to an iridium(III) complex. η6-Coordination of the arene increases its electrophilicity and allows for high positional selectivity of hydroxylation at the site of least electron density. Through investigation of intermediate η5-cyclohexadienyl adducts and arene exchange reactions, we evaluate incorporation of arene π-activation into a catalytic cycle for C-H functionalization.
- D'Amato, Erica M.,Neumann, Constanze N.,Ritter, Tobias
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supporting information
p. 4626 - 4631
(2015/10/06)
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- Pyrimidone-based series of glucokinase activators with alternative donor-acceptor motif
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Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.
- Filipski, Kevin J.,Guzman-Perez, Angel,Bian, Jianwei,Perreault, Christian,Aspnes, Gary E.,Didiuk, Mary T.,Dow, Robert L.,Hank, Richard F.,Jones, Christopher S.,Maguire, Robert J.,Tu, Meihua,Zeng, Dongxiang,Liu, Shenping,Knafels, John D.,Litchfield, John,Atkinson, Karen,Derksen, David R.,Bourbonais, Francis,Gajiwala, Ketan S.,Hickey, Michael,Johnson, Theodore O.,Humphries, Paul S.,Pfefferkorn, Jeffrey A.
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p. 4571 - 4578
(2013/08/15)
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- 2-(3,5-DISUBSTITUTEDPHENYL)PYRIMIDIN-4(3H)-ONE DERIVATIVES
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O N NH R3 R2 O R1 168 ABSTRACT The present invention provides a 2-(3,5-disubstitutedphenyl)pyrimidin- 4(3H)-one compound of Formula (I) 5 (I) or a pharmaceutically acceptable salt thereof wherein R 1, R2 and R3 are as defined herein. The compounds of Formula (I) have been found to act as glucokinase activators. Consequently, the compounds of Formula (I) and 10 the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucokinase.
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Page/Page column 59-60
(2012/01/06)
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- IMIDAZOLIDINEDIONE DERIVATIVES
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The invention provides a compound of formula (Ia), and pharmaceutically acceptable salts thereof. The invention also provides use of the compounds or salts as modulators of Kv3.1 and/or Kv3.2, and in the treatment of diseases or disorders where a modulator of Kv3.1 and/or Kv3.2 is required, such as depression and mood disorders, hearing disorders, schizopherenea, substance abuse disorders, sleep disorders or epilepsy.
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Page/Page column 49
(2011/06/26)
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- Mild debenzylation of aryl benzyl ether with BCl3 in the presence of pentamethylbenzene as a non-lewis-basic cation scavenger
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Scope and limitations of the debenzylation conditions for aryl benzyl ether, which was developed during our synthetic studies on yatakemycin, were investigated. The chemoselective debenzylation proceeds at low temperature with a combination of BCl3 and pentamethylbenzene as a cation scavenger in the presence of various functional groups.
- Okano, Kentaro,Okuyama, Kei-Ichiro,Fukuyama, Tohru,Tokuyama, Hidetoshi
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scheme or table
p. 1977 - 1980
(2009/04/07)
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- NOVEL ACETYL-COA CARBOXYLASE (ACC) INHIBITORS AND THEIR USE IN DIABETES, OBESITY AND METABOLIC SYNDROME
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The present invention relates to compounds of formula (I) which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.
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Page/Page column 22
(2008/06/13)
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- The desymmetrisation of resorcinol: The synthesis of resorcinol monoalkyl ethers
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The desymmetrisation of resorcinol to give 3-alkoxyresorcinol derivatives can be achieved in excellent yields either from resorcinol monobenzoate and alcohols using Mitsunobu reactions followed by hydrolysis using a strong base or by using 3-iodophenylbenzyl ether as a resorcinol monobenzyl ether equivalent in reactions with alcohols catalysed by copper(I)-9,10-phenanthroline followed by ammonium formate-palladium catalysed hydrogenolysis.
- Boxhall, Jonathan Y.,Page, Philip C. Bulman,Chan, Yohan,Hayman, Colin M.,Heaney, Harry,McGrath, Matthew J.
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p. 997 - 1001
(2007/10/03)
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- SELECTIVE DEALKYLATIONS OF ARYL ALKYL ETHERS AND THIOETHERS BY SODIUM IN HMPA
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The reaction of sodium with bis- and tris(alkoxy)benzenes in HMPA gives selectively the products of monodealkylation.The reaction proceeds through a dianion which fragments into an alkyl and an aryloxy anion.The positional selectivity of this fragmentation is governed by the structure of both the alkyl and aryloxy groups.With bis- and tris(alkoxy)benzenes which for symmetry reasons can afford aryloxy anions having the same basicity, the dealkylation involves exlusively the less substituted alkyl group.On the contrary, in the asymmetric terms, the positional selectivity of the dealkylation process is governed by the basicity of the aryloxy anion.On the basis of these concepts several efficient and synthetically useful reactions have been developed.In most cases the selectivity obtained in the present reactions in different from that observed with other previously developed methods which use sodium methoxide or sodium alkenethiolates in HMPA.It is shown that the appropriate choice of the reagent allows selective dealkylation of the desired alkoxy group of a poly(alkoxy)benzene.The reaction of sodium with bis(alkylthio)benzenes in HMPA gives the bis(mercapto)benzenes.If the reduction is carried out with a solution of sodium in HMPA, the reaction gives instead the products of monodealkylation.This however is not selective.It is suggested that in the case of thioethers the dealkylation products originate from the fragmentation of the radical anions.
- Testaferri, L.,Tiecco, M.,Tingoli, M.,Chianelli, D.,Montanucci, M.
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p. 3687 - 3692
(2007/10/02)
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