- Discovery of novel N-sulfonamide-tetrahydroquinolines as potent retinoic acid receptor-related orphan receptor γt inverse agonists for the treatment of autoimmune diseases
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Targeting the nuclear receptor RORγt is thought to be effective in autoimmune disorders. Tertiary sulfonamide 1 was found to be a potent RORγt inverse agonist previously. However, the high hepatic clearance value limits its druggability. In this study, we designed and synthesized a series of N-sulfonamide-tetrahydroquinolines by molecular modeling and scaffold hopping strategy, aiming at improving the metabolic stabilities. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 13 with moderate binding affinity and inhibitory activity of Th17 cell differentiation. Binding mode of 13 with RORγt-LBD was revealed by molecular docking. Moreover, 13 showed lower intrinsic clearance in mouse liver microsomes compared with 1 and potent in vivo efficacy and safety in psoriasis models, which can be used as a good starting point for the further optimization.
- Sun, Nannan,Ma, Xiaojun,Zhou, Kaifeng,Zhu, Chen,Cao, Zhonglian,Wang, Yonghui,Xu, Jun,Fu, Wei
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- TETRAHYDRO-BENZOAZEPINE GLYCOSIDASE INHIBITORS
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Compounds of formula (I') wherein A, R1, R2, T1, T2, T3, T4, L, W, Z, R''', m and n have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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Page/Page column 133
(2020/03/15)
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- TETRAHYDRO-BENZO[D]AZEPINE DERIVATIVES AS GPR120 MODULATORS
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Novel tetrahydroisoquinoline and tetrahydrobenzazepine compounds of formula (I) capable of modulating the G-protein-coupled receptor GPR120, compositions comprising the compounds, and methods for their use for controlling insulin levelsin vivoand for the treatment of conditions such as of diabetes, inflammation, obesity and metabolic diseases. (I)
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Page/Page column 137-138
(2018/10/19)
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- RESORCINOL DERIVATIVE AS HSP90 INHIBITOR
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The present invention relates to a compound represented by formula (I) of a resorcinol derivative as an HSP90 inhibitor or pharmaceutically accepted salts thereof. The compound in the present invention has the activity of inhibiting heat shock protein HSP90. Therefore, the compound in the present invention is used to treat proliferative diseases such as cancer and neurodegenerative diseases. The present invention further provides the compounds and preparation methods for pharmaceutical compositions comprising the compounds, a method for treating diseases, and pharmaceutical compositions comprising the compounds.
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Paragraph 0099
(2017/12/27)
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- Potent histone deacetylase inhibitors derived from 4-(aminomethyl)-N- hydroxybenzamide with high selectivity for the HDAC6 isoform
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A screen for HDAC6 inhibitors identified acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide as potent leads with unexpected selectivity over the other subtypes. We designed and synthesized constrained heterocyclic analogues such as tetrahydroisoquinolines that show further enhanced HDAC6 selectivity and inhibitory activity in cellular assays. Selectivity may be attributed to the benzylic spacer more effectively accessing the wider channel of HDAC6 compared to other HDAC subtypes as well as hydrophobic capping groups interacting with the protein surface near the rim of the active site.
- Blackburn, Christopher,Barrett, Cynthia,Chin, Janice,Garcia, Kris,Gigstad, Kenneth,Gould, Alexandra,Gutierrez, Juan,Harrison, Sean,Hoar, Kara,Lynch, Chrissie,Rowland, R. Scott,Tsu, Chris,Ringeling, John,Xu, He
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p. 7201 - 7211
(2013/10/21)
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- SUBSTITUTED HYDROXAMIC ACIDS AND USES THEREOF
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This invention provides compounds of formula (/): wherein R1, R2, G, m, n, p and q have values as described in the specification, useful as inhibitors of HDAC6. The invention also provides pharmaceutical compositions comprising the c
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Page/Page column 143-144
(2011/01/12)
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- Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261 as adenosine A2A receptor antagonists
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SCH 58261 is a reported adenosine A2A receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A1 receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A2A receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A2A receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 μM at physiological pH.
- Shah, Unmesh,Lankin, Claire M.,Boyle, Craig D.,Chackalamannil, Samuel,Greenlee, William J.,Neustadt, Bernard R.,Cohen-Williams, Mary E.,Higgins, Guy A.,Ng, Kwokei,Varty, Geoffrey B.,Zhang, Hongtao,Lachowicz, Jean E.
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scheme or table
p. 4204 - 4209
(2009/04/10)
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- Antibacterial agents
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Compounds of formula I and methods for their preparation are disclosed. Further disclosed are methods of making biologically active compounds of formula I as well as pharmaceutically acceptable compositions comprising compounds of formula I. Compounds of formula I as disclosed herein can be used in a variety of applications, including using the invention compounds to treat bacterial infections.
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Page/Page column 24
(2008/06/13)
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- OXAZOLIDINONE DERIVATIVES N-SUBSTITUTED BY A BICYCLIC RING, FOR USE AS ANTIBACTERIAL AGENTS
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Compounds of formula (I) and methods for their preparation are disclosed. Further disclosed are methods of making biologically active compounds of formula (I) as well as pharmaceutically acceptable compositions comprising compounds of formula (I). Compoun
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Page/Page column 109
(2010/02/08)
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