- Design, synthesis and biological evaluation of novel thiohydantoin derivatives as potent androgen receptor antagonists for the treatment of prostate cancer
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Prostate cancer (PC) is the most common malignancy in men worldwide. Here, two series of novel thiohydantoin derivatives of enzalutamide as potent androgen receptor (AR) antagonists were designed and synthesized. Among them, compound 31c was identified as an AR antagonist which is 2.3–fold more potent than enzalutamide. Molecular docking studies were performed to explain the improved potency of 31c at AR. In cell proliferation assays, 31c exhibited similar anti-proliferative activities with enzalutamide against hormone sensitive LNCaP cells and AR-overexpressing LNCaP/AR cells. These data indicate that 31c can be a good lead compound for further structure optimization for the treatment of prostate cancer.
- Wang, Ao,Wang, Yawan,Meng, Xin,Yang, Yushe
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- PHTHALAZINE DERIVATIVES OF FORMULA (I) AS PCAF AND GCN5 INHIBITORS FOR USE IN THE TREATMENT OF CANCER
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The present invention relates to methods for treating PCAF and GCN5 mediated disorders using a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein ring A, R1, R3, R4, R5, and each Re have any of the values defined in the specification. Also included are novel compounds of Formula (I) and salts thereof, as well as pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
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Page/Page column 69
(2016/03/19)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column
(2015/03/31)
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- Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: Synthesis, biological characterization, and behavioral studies
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Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia.
- Brindisi, Margherita,Butini, Stefania,Franceschini, Silvia,Brogi, Simone,Trotta, Francesco,Ros, Sindu,Cagnotto, Alfredo,Salmona, Mario,Casagni, Alice,Andreassi, Marco,Saponara, Simona,Gorelli, Beatrice,Weikop, Pia,Mikkelsen, Jens D.,Scheel-Kruger, Jorgen,Sandager-Nielsen, Karin,Novellino, Ettore,Campiani, Giuseppe,Gemma, Sandra
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p. 9578 - 9597
(2015/01/09)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column 64
(2013/07/31)
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- Design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as γ-secretase inhibitors
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γ-Secretase is a key enzyme involved in the production of β-amyloid peptides which are believed to play a critical role in the onset and progression of Alzheimer's disease (AD). As such, inhibition of γ-secretase has been an attractive approach to AD ther
- Guo, Tao,Gu, Huizhong,Hobbs, Doug W.,Rokosz, Laura L.,Stauffer, Tara M.,Jacob, Biji,Clader, John W.
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p. 3010 - 3013
(2008/02/05)
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- Design, synthesis, and evaluation of tetrahydroquinoline-linked thiazolidinedione derivatives as pparγ selective activators
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A series of tetrahydroqninoline-linked thiazolidinediones was designed and synthesized and their peroxisome proliferator activated receptor-γ (PPARγ) agonistic activities were evaluated. A number of analogs were revealed to have significant PPARγ agonisti
- Kim, HyeSung,Gim, HyoJin,Yang, Mihi,Ryu, Jae-Ha,Jeon, Raok
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p. 2131 - 2154
(2008/09/17)
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- Fused bicyclic carboxamide derivatives and methods of their use
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Fused bicyclic carboxamide derivatives are disclosed. Pharmaceutical compositions containing the compounds and methods for their use are also disclosed.
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Page/Page column 49-50
(2010/02/11)
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- Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives as novel muscarinic receptor antagonists
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In the course of continuing efforts to develop potent and bladder-selective muscarinic M3 receptor antagonists, quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives and related compounds were designed as conformationally restricted analogues of quinuclidin-3-yl benzhydrylcarbamate (8). Binding assays with rat muscarinic receptor subtypes revealed that the quinuclidin-3-yl 1-aryl-1,2,3,4- tetrahydroisoquinoline-2-carboxylate derivatives showed high affinities for the M3 receptor, and selectivity for the M3 receptor over the M2 receptor. Of these derivatives, (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate monohydrochloride (9b) exhibited almost the same inhibitory activity against bladder contraction to that of oxybutynin (1), and more than 10-fold selectivity for bladder contraction versus salivary secretion, demonstrating that 9b may be useful for the treatment of symptoms associated with overactive bladder without having side effects such as dry mouth.
- Naito, Ryo,Yonetoku, Yasuhiro,Okamoto, Yoshinori,Toyoshima, Akira,Ikeda, Ken,Takeuchi, Makoto
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p. 6597 - 6606
(2007/10/03)
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- Solvent dependent regioselective hydrogenation of substituted quinolines
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Various substituted quinolines have been reduced under H2 using Rh/Al2O3. Using methanol as solvent leads selectively to the 1,2,3,4-tetrahydroquinoline derivatives whereas in hexafluoroisopropanol the decahydro compounds are obtained.
- Fache, Fabienne
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p. 2827 - 2829
(2007/10/03)
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- Cyclic amino acid compounds pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
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Disclosed are compounds which inhibit β-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits β-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.
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- Enzymatic resolution of 2-substituted tetrahydroquinolines. Convenient approaches to tricyclic quinoxalinediones as potent NMDA-glycine antagonists
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Two approaches leading to the enantiomerically pure tricyclic quinoxalinedione class of NMDA-glycine antagonists using enzymatic resolutions are described. An intermediate, racemic methyl 1,2,3,4- tetrahydroquinoline-2-carboxylate 3, was resolved to (S)-3
- Katayama, Seiji,Ae, Nobuyuki,Nagata, Ryu
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p. 4295 - 4299
(2007/10/03)
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- Synthesis of Benzo-Fused, 7,5- and 7,6-Fused Azepinones as Conformationally Restricted Dipeptide Mimetics
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Methodology for the generation of novel conformationally restricted dipeptide mimetics 9 and 16 has been developed.The key step involved intramolecular addition of an oxonium ion to the proximal indoline/tetrahydroquinoline aromatic ring.A dramatic differ
- Robl, Jeffrey A.,Karanewsky, Donald S.,Asaad, Magdi M.
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p. 1593 - 1596
(2007/10/02)
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- An Improved Synthesis of Homoproline and Derivatives
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An improved, general synthesis of substituted homoprolines has been developed by using readily available substituted pyridines (1).A key step in this synthetic procedure involves the known conversion of pyridine-N-oxides to 2-cyanopyridines (3) in nearly quantitative yields.The resulting nitriles are hydrolyzed to the corresponding pyridine-2-carboxylic acids (4).Subsequent reduction of the aromatic ring with PtO2/H2 gives the homoprolines (5) in good yields as racemic cis isomers.This procedure also can be utilized for the preparation of 5,6-benzohomoprolines fromthe appropriate quinoline precursors.The N-tert-butyloxycarbonyl (Boc) derivatives of these amino acids (useful intermediates for peptide synthesis) were also prepared in good yields.
- Shuman, Robert T.,Ornstein, Paul L.,Paschal, Jonathan W.,Gesellchen, Paul D.
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p. 738 - 741
(2007/10/02)
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- Reduction of Quinolinecarboxylic Acids by Raney Alloy
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The heterocyclic nucleus in quinolinecarboxylic acids is reduced by Raney alloy (nickel-aluminium) in alkaline media to give 1,2,3,4-tetrahydro-2-,3-,4-,5-,6-, and 8-quinolinecarboxylic acids and 8-methyl-5-quinolinecarboxylic acid and their ethyl esters.
- Gracheva, I. N.,Tochilkin, A. I.
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