- Synthesis and evaluation of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives as xanthine oxidase inhibitors
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This study mainly focused on the modification of the X2 position in febuxostat analogs. A series of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives (1a-s) with an N atom occupying the X2 position was designed and synthesized. Evaluation of their inhibitory potency in vitro on xanthine oxidase indicated that these compounds exhibited micromolar level potencies, with IC50 values ranging from 0.21?μM to 26.13?μM. Among them, compound 1s (IC50?=?0.21?μM) showed the most promising inhibitory effects and was 36-fold more potent than allopurinol, but was still 13-fold less potent than the lead compound Y-700, which meant that a polar atom fused at the X2 position could be unfavorable for potency. The Lineweaver-Burk plot revealed that compound 1s acted as a mixed-type xanthine oxidase inhibitor. Analysis of the structure-activity relationships demonstrated that a more lipophilic ether tail (e.g., meta-methoxybenzoxy) at the 4′-position could benefit the inhibitory potency. Molecular modeling provided a reasonable explanation for the structure–activity relationships observed in this study.
- Zhang, Ting-jian,Wu, Qing-xia,Li, Song-ye,Wang, Lin,Sun, Qi,Zhang, Yi,Meng, Fan-hao,Gao, Hua
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supporting information
p. 3812 - 3816
(2017/07/27)
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- Non-steroidal dissociated glucocorticoid agonists: Indoles as A-ring mimetics and function-regulating pharmacophores
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We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.
- Betageri, Raj,Gilmore, Thomas,Kuzmich, Daniel,Kirrane, Thomas M.,Bentzien, J?rg,Wiedenmayer, Dieter,Bekkali, Younes,Regan, John,Berry, Angela,Latli, Bachir,Kukulka, Alison J.,Fadra, Tazmeen N.,Nelson, Richard M.,Goldrick, Susan,Zuvela-Jelaska, Ljiljana,Souza, Don,Pelletier, Josephine,Dinallo, Roger,Panzenbeck, Mark,Torcellini, Carol,Lee, Heewon,Pack, Edward,Harcken, Christian,Nabozny, Gerald,Thomson, David S.
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scheme or table
p. 6842 - 6851
(2011/12/22)
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- NOVEL AMIDE COMPOUNDS WITH MCH ANTAGONISTIC EFFECT AND MEDICAMENTS COMPRISING SAID COMPOUNDS
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The invention relates to amide compounds of general formula (I), in which the groups and residues A, B, b, W, X, Y, Z, R1, R2 and R3 have the meanings given in claim 1. The invention further relates to medicaments comprising at least one of said amides. Said medicaments are suitable for the treatment of metabolic disorders and/or eating disorders, in particular, obesity, bulimia, anorexia, hyperphagia, and diabetes as a result of the MCH receptor antagonism.
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Page/Page column 88
(2008/06/13)
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- IL-8 receptor antagonists
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This invention relates to novel compounds, pharmaceutical compositions comprising these compounds and their use in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).
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- IL-8 RECEPTOR ANTAGONISTS
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Novel IL-8 receptor antagonists and methods of using them are provided.
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- IL-8 RECEPTOR ANTAGONISTS
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The present invention relates to novel compounds and a novel use of phenyl ureas in the treatment of disease states mediated by the chemokine Interleukin-8 (IL-8).
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- IL-8 RECEPTOR ANTAGONISTS
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This invention relates to the novel use of phenyl ureas in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).
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- IL-8 RECEPTOR ANTAGONISTS
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This invention relates to novel compounds and a novel use of phenyl ureas in the treatment of disease scates mediated by the chemokine, Interleukin-8 (IL-8). In particular, this invention relates to the novel compounds of Formula (Ia) and their use in treating chemokine mediated diseases wherein the chemokine binds to an IL-8 a or b receptor. Compounds of Formula (Ia) are represented by the structure: STR1 wherein interalia, X is oxygen or sulfur;Rb is NR 6 R. sub.7, alkcyl, aryl, arylC 1-4 alkyl, aryl C 2-4 alkenyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4 alkenyl, heterocyclic or heterocyclic C 1-4 alkyl, or a heterocyclic C 2-4 alkenyl moiety, camphor, all of which may be optionally substituted; R 1 is independently selected from hydrogen; halogen; nitro; cyano; C 1-10 alkyl; halosubstituted C 1-10 alkyl; C 2-10 alkoxy; halosubstituted C 1-10 alkoxy; azide; (CR. sub.8 R 8)q S(O) t R 4 ; hydroxy; hydroxy substituted C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryl C 2-10 alkenyl; aryloxy; aryl C 1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C 2-10 alkenyl; heteroaryl C 1-4 alkyloxy; heterocyclic; heterocyclic C 1-4 alkyl; heterocyclicC 1-4 alkyloxy; heterocyclic C 2-10 alkenyl; q is 0 or an integer having a value of 1 to 10; n is an integer having a value of 1 to 3;m is an integer having a value of 1 to 3; Y is hydrogen; halogen; nitro; cyano; halosubstituted C 1-10 alkyl; C 1-10 alkyl; C 2-10 alkenyl C. sub.1-10 alkoxy; halosubstituted C 1-10 alkoxy; azide; (CR 8 R. sub.8)qS(O) t R 4, (CR 8 R 8)qOR 4 ; hydorxy; hydroxy substituted C. sub.1-4 alkyl; aryl; aryl C 1-4 alkyl; aryloxy; arylC. sub.1-4 alkyloxy; aryl C 2-10 alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C 1-4 alkyloxy; heteroaryl C 2-10 alkenyl; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclicC 2-10 alkenyl;or a pharmaceutically acceptable salt thereof.
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- Aromatic Nitro-group Displacement Reactions. Part 3. Minor Products of the o-Cyanophenol Synthesis
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In dipolar aprotic solvents, the action of cyanide ions on a moderately activated aromatic or heteroaromatic nitro-compound yields, in addition to the o-cyanophenol, a range of products generated through nitro-group reduction.
- Gorvin, John H.
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p. 738 - 762
(2007/10/02)
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