- Novel propanamides as fatty acid amide hydrolase inhibitors
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Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroaryl)-2-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or non-competitive (TPA14) inhibition modes.
- Deplano, Alessandro,Morgillo, Carmine Marco,Demurtas, Monica,Bj?rklund, Emmelie,Cipriano, Mariateresa,Svensson, Mona,Hashemian, Sanaz,Smaldone, Giovanni,Pedone, Emilia,Luque, F. Javier,Cabiddu, Maria G.,Novellino, Ettore,Fowler, Christopher J.,Catalanotti, Bruno,Onnis, Valentina
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p. 523 - 542
(2017/05/29)
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- Application of the mild-condition phthalimidine synthesis with use of 1,2,3-1h-benzotriazole and 2-mercaptoethanol as dual synthetic auxiliaries. Effective synthesis of phthalimidines possessing a variety of substituents at 2-position
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The mild-condition phthalimidine synthesis based on Mannich type 1:1 condensation reaction between o-phthalaldehyde with a variety of primary amines in the presence of excess 2-mercaptoethanol and 1,2,3-1H-benzotriazole as "dual synthetic auxiliaries" in MeCN for 13 h at room temperature afford 2-substituted phthalimidines (2,3-dihydroisoindol-1-one) in fair to good isolated yields.
- Takahashi, Ichiro,Kawakami, Teruki,Hirano, Etsushi,Kimino, Mako,Kamimura, Shigeki,Miwa, Takayuki,Tamura, Takanori,Tazaki, Ryo,Kitajima, Hidehiko,Hatanaka, Minoru,Isa, Kimio,Hosoi, Shinzo
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p. 557 - 571
(2017/04/10)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kirl.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and conditions associated with excessive salt and water retention.
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Page/Page column 89
(2014/07/08)
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- RETINOID-RELATED ORPHAN RECEPTOR GAMMA MODULATORS, COMPOSITION CONTAINING THEM AND USES THEREOF
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Provided are retinoid-related orphan receptor gamma(ROR γ) modulators of formula (I), processes for their preparation, pharmaceutical compositions containing them, and their uses in the treatment of diseases mediated by ROR γ.
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Page/Page column 40
(2012/08/08)
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- METHODS AND SYSTEMS FOR TREATING CELL PROLIFERATION DISORDERS WITH PSORALEN DERIVATIVES
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Psoralen compounds of Formula (I): wherein (N+ Aryl) is a member selected from the group consisting of nitrogen containing aromatic heterocycles of formulae (i)-(iii): wherein Z is a group of formula: wherein R is C1-C30 hydrocarbyl, which may be linear, branched or cyclic and contains from 1 to 15 carbon-carbon double bonds, which may be conjugated or unconjugated with one another or may include an aryl ring, and may contain one or more substituents; R1 is hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkene-aryl, alkene-heteroaryl, alkene-heterocyclyl, alkene-cycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, fused heterocyclyheteroaryl, alkylene-fused cycloalkylaryl, alkylene-fused cycloalkylheteroaryl, alkylene-fused heterocyclylaryl, alkylene-fused heterocyclyheteroaryl; n is an integer from 1 to 8 and X is a pharmaceutically acceptable counter ion; and their use in methods for the treatment of a cell proliferation disorder in a subject, pharmaceutical compositions containing the psoralen derivatives, a kit for performing the method, and a method for causing an autovaccine effect in a subject using the method.
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- Vanilloid Receptor Ligands, Pharmaceutical Compositions Containing Them, Process for Making Them, and Use Thereof for Treating Pain and Other Conditions
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Vanilloid receptor ligand compounds corresponding to formula I: pharmaceutical compositions containing such compounds, a process for producing such compounds, and methods of using such compounds for treating or inhibiting pain and various other disorders or conditions.
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Page/Page column 39; 46; 56
(2009/07/03)
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- Methods and compositions employing 4-aminophenylacetic acid compounds
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The invention provides compositions comprising 4-APAA compounds and methods for treating disorders involving inflammation of the digestive system and/or mucosal tissues, such as inflammatory bowel disease. The methods and compositions of the invention also include combinations of 4-APAA compounds and 5-ASA compounds for treatment of such disorders.
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Page/Page column 10
(2008/06/13)
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- Amphiphilic pyridinium salts block TNFα/NFκB signaling and constitutive hypersecretion of interleukin-8 (IL-8) from cystic fibrosis lung epithelial cells
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Cystic fibrosis (CF) is a common, lethal genetic disease, which is due to mutations in the CFTR gene. The CF lung expresses a profoundly proinflammatory phenotype, due to constitutive hypersecretion of IL-8 from epithelial cells lining the airways. In a systematic search for candidate drugs that might be used therapeutically to suppress IL-8 secretion from these cells, we have identified a potent and efficacious series of amphiphilic pyridinium salts. The most potent of these salts is MRS2481, an (R)-1-phenylpropionic acid ester, with an IC50 of ca. 1 μM. We have synthesized 21 analogues of MRS2481, which have proven sufficient to develop a preliminary structure-activity relationship (SAR). For optimal activity, we have found that the ester must be connected to the pyridinium derivative by an eight-carbon chain. An optical isomer of the lead compound, containing an (S)-1-phenylpropionic acid ester, has been found to be a much less active. The mechanism of action of MRS2481 appears to involve inhibition of signaling of the NFκB and AP-1 transcription factors to the IL-8 promoter. MRS2481 is a potent inhibitor of TNFα-induced phosphorylation and proteosomal destruction of IκBα. Inasmuch as IκBα is the principal inhibitor of the NFκB signaling pathway, preservation of intact IκBα would serve to keep the IL-8 promoter silent. We also find that MRS2481 blocks TNFα-activated phosphorylation of JNK, the c-JUN kinase. The IL-8 promoter is also activated by an AP-1 site, which requires a phospho-c-JUN/c-FOS dimer for activity. We therefore interpret these data to suggest that the mechanism of MRS2481 action is to inhibit both NFκB and AP-1 signaling on the IL-8 promoter. Given the medicinally promising properties of water-solubility, potency in the low μM concentration range, and high efficacy, we anticipate that MRS2481, or a further optimized derivative, may find an important place in the armamentarium of pharmaceutical strategies yet to be arrayed against the inflammatory phenotype of the CF lung.
- Tchilibon, Susanna,Zhang, Jian,Yang, QingFeng,Eidelman, Ofer,Kim, Haksung,Caohuy, Hung,Jacobson, Kenneth A.,Pollard, Bette S.,Pollard, Harvey B.
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p. 381 - 393
(2007/10/03)
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- Phenylacetamido-pyrazole derivatives, process for their preparation and their use as antitumor agents
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Compounds represented by formula (I) wherein R is a C3-C5cycloalkyl group, R1is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof; are useful in the treatment of cell proliferative disorders, e.g. cancer, associated with an altered cell cycle dependent kinase activity.
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- Immunoregulatory compounds and derivatives and methods of treating diseases therewith
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Compounds are disclosed having the structure of Formula I: where R1, R3, and R4 are independently hydrogen or C1 to C4 alkyl, and R2 is: where R5 is selected from the group consisting of hydrogen and C1 to C4 alkyl, or where R6, R7 and R8 are independently hydrogen or C1 to C4 alkyl; or the esters or pharmacologically acceptable salts thereof. Such compounds may be utilized for the prophylaxis or treatment of various diseases, particularly inflammatory conditions of the GI tract. Methods of treating inflammatory conditions of the GI tract such as inflammatory bowel disease using compounds having the following formula are also disclosed: where R9, R10 and R11 are independently selected from the group consisting of hydrogen and C1 to C4 alkyl, and R12 is selected from the group consisting of hydrogen and —C(O)R13, where R13 is a C1 to C6 alkyl or an aryl group.
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- Application of the phthalimidine synthesis with use of 1,2,3-1 H-benzotriazole and 2-mercaptoethanol as dual synthetic auxiliaries. Part 1. A simple synthesis of (±)-Indoprofen
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A representative nonsteroidal anti-inflammatory drug indoprofen is prepared in 4 steps from the commercially available 2-(4-nitrophenyl)propanoic acid. The key step is the mild phthalimidine synthesis by the double Mannich condensation of o-phthalaldehyde with ethyl 2-(4-aminophenyl)propanoate with use of 1,2,3-1H-benzotriazole and 2-mercaptoethanol as dual synthetic auxiliaries.
- Takahashi, Ichiro,Hirano, Etsushi,Kawakami, Teruki,Kitajima, Hidehiko
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p. 2343 - 2346
(2007/10/03)
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- Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 1. Tropic and 2-phenylpropionic acid esters
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Previous studies have shown that (R)-(+)-hyoscyamine has analgesic activity as a consequence of increased ACh release following antagonism of central muscarinic autoreceptors. Since the enhancement of central cholinergic transmission could be beneficial for cognitive disorders, we manipulated (R)-(+)-hyoscyamine, synthesizing several derivatives of tropic and 2-phenylpropionic acids, with the aim of obtaining drugs which are able to increase ACh release and consequently to show analgesic and nootropic activities. The results showed that several new compounds are indeed potent analgesics (with an analgesic efficacy comparable to that of morphine) and that the most potent one ((±)-19, PG9) also has remarkable cognition- enhancing properties. Our study confirmed that the mechanism of action involves ACh release even if it is still unclear whether only muscarinic autoreceptors or, also, heteroreceptors are involved.
- Gualtieri,Conti,Dei,Giovannoni,Nannucci,Romanelli,Scapecchi,Teodori,Fanfani,Ghelardini,Giotti,Bartolini
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p. 1704 - 1711
(2007/10/02)
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- α-Methylated Analogues of Triiodothyroalkanoic Acids: Synthesis and Biological Activity
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Three novel thyroid hormone analogues: α-methyl-3,5,3'-triiodothyroacetic acid, α-methyl-3,5,3'-triiodothyropropionic acid and α-methyl-3,5,3',5'-tetraiodothyropropionic acid were synthesized.The hepatic thyroid receptor affinity of these analogues was compared to that other available thyroid analogues.The ability of these compounds to increase the activity of two hepatic enzymes and to lower blood cholesterol was compared to that of L-triiodothyronine. α-Methyl-3,5,3'-triiodothyroacetic acid was shown to have less nuclear binding affinity, less enzyme inducing ability, but more blood cholesterol lowering ability than triiodothyroacetic acid. α-Methyl-3,5,3',5'-tetraiodothyropropionic acid showed less nuclear binding affinity and less enzyme-inducing activity than α-methyl-3,5,3'-triiodothyropropionic acid.
- Zenker, N.,Ekpe, A. E.,Hubbard, L. S.
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p. 548 - 552
(2007/10/02)
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- Protection of Primary Amines as N-Substituted 2,5-Dimethylpyrroles
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Protection of primary amine group is achieved by incorporating it into an N-substituted 2,5-dimethylpyrrole system.The method affords protection against strong bases and nucleophiles, heating with concentrated alkali, standard mineral acid work-up conditions, and various other reagents.Phenyl-, pyridil-, thiazolyl-, and alkyl-amines have been studied.All give trisubstituted pyrroles in high yield (>80percent) by reaction with hexane-2,5-dione.The pyrroles from the first three types are stable to storage; even the N-alkyl compounds can be used without difficulty.Regeneration of the amine group, by treatment with hydrxylamine hydrochloride, is efficient (80percent yield) with the phenyl, pyridyl, and alkyl compounds but less satisfactory (60 - 65percent generally but down to 25percent in two cases) with the thiazolyl derivatives.
- Bruekelman, Stephen P.,Leach, (Miss) Susan E.,Meakins, G. Denis,Tirel, Malcolm D.
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p. 2801 - 2807
(2007/10/02)
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