- MALIC ENZYME INHIBITORS
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The present invention relates to novel compounds useful as malic enzyme (ME) inhibitors, processes for their preparation and use of these compounds for the therapeutic treatment of disorders mediated by ME such as cancers (e.g. pancreatic ductal adenocarcinoma (PDAC)) in humans.
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Page/Page column 95-96
(2021/04/23)
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- 5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2 inhibitors: Improved brain unbound fraction enables efficacy
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We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h.
- Ding, Xiao,Stasi, Luigi Piero,Dai, Xuedong,Long, Kai,Peng, Cheng,Zhao, Baowei,Wang, Hailong,Sun, Changhui,Hu, Huan,Wan, Zehong,Jandu, Karamjit S.,Philps, Oliver J.,Chen, Yan,Wang, Lizhen,Liu, Qian,Edge, Colin,Li, Yi,Dong, Kelly,Guan, Xiaoming,Tattersall, F. David,Reith, Alastair D.,Ren, Feng
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supporting information
p. 212 - 215
(2018/12/11)
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- Discovery of 5-substituent-N-arylbenzamide derivatives as potent, selective and orally bioavailable LRRK2 inhibitors
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Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson's disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability.
- Ding, Xiao,Dai, Xuedong,Long, Kai,Peng, Cheng,Andreotti, Daniele,Bamborough, Paul,Eatherton, Andrew J.,Edge, Colin,Jandu, Karamjit S.,Nichols, Paula L.,Philps, Oliver J.,Stasi, Luigi Piero,Wan, Zehong,Xiang, Jia-Ning,Dong, Kelly,Dossang, Pamela,Ho, Ming-Hsun,Li, Yi,Mensah, Lucy,Guan, Xiaoming,Reith, Alastair D.,Ren, Feng
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supporting information
p. 4034 - 4038
(2017/08/23)
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- Novel benzoxazolone compound
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PROBLEM TO BE SOLVED: To provide a therapeutic agent for diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small diameter fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria or multiple sclerosis. SOLUTION: There is provided a benzoxazolone compound represented by the formula (1) or a pharmaceutically acceptable salt. (1), where R1 and R2 are each independently H or C1-6 alkyl, where the alkyl may be substituted by hydroxy, C1-4 alkylsulfonyl, aminocarbonyl or 4 to 7-membered heterocycloalkyl, or the like, L is C1-6 alkylene, R3 is C1-6 alkyl, C3-7 cycloalkyl, where the cycloalkyl may be substituted by halogen or hydroxy or the like, C6-10 aryl, where the aryl may be substituted by halogen, C1-4 alkyl or C1-4 haloalkyl or the like, R4 is H, halogen or C1-4 alkyl. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0462; 0463
(2017/04/27)
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- NOVEL COMPOUNDS
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The present invention discloses novel compounds inhibiting LRRK2 kinase activity, the preparation processes thereof, the compositions containing them, as well as the use in treating diseases characterized by LRRK2 kinase activity, particularly Parkinson's disease and Alzheimer's disease.
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Page/Page column 49
(2011/04/25)
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