- Accelerated Discovery of Novel Ponatinib Analogs with Improved Properties for the Treatment of Parkinson's Disease
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Parkinson's disease (PD) is a debilitating and common neurodegenerative disease. New insights implicating c-Abl activation as a driving force in PD have opened a new drug development avenue for PD treatment beyond the symptomatic relief by L-DOPA. BCR-Abl inhibitors, which include nilotinib and ponatinib, have been found to inhibit this process, and nilotinib has shown improvement in outcomes in a 12-patient, nonrandomized trial. However, nilotinib is a potent inhibitor of hERG, a cardiac K+ channel whose inhibition increases risk of sudden death. We used our machine learning approach to predict novel molecules that would inhibit c-Abl while also having minimal liability against hERG. Of our six novel compounds tested, we identified two that had c-Abl potencies comparable to nilotinib, but with significantly improved profiles regarding the hERG channel. Our best compound exhibited a hERG IC50 of 12.1 μM (compared to nilotinib with an IC50 of 0.45 μM and ponatinib with IC50 of 0.767 μM). This work is a step forward for a machine learning enabled, multiparameter optimization of a chemical space and represents a significant advance in the development of novel Parkinson's therapies.
- Kaiser, Thomas M.,Dentmon, Zackery W.,Dalloul, Christopher E.,Sharma, Savita K.,Liotta, Dennis C.
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supporting information
p. 491 - 496
(2020/04/30)
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- ABELSON NON-TYROSINE KINASE COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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The present disclosure relates to compounds for the use of treating neurodegenerative diseases and, in particular, to compounds targeting the Abelson non-tyrosine kinase (c-Abl) protein for such treatment. The neurological disorders and conditions include Parkinson's disease, Alzheimer's disease and the like. It also relates to pharmaceutical compositions and methods of treatment of such neurological disorders involving the c-Abl protein kinase.
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Page/Page column 22-23
(2020/10/28)
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- Tandem Pd-catalyzed C-C coupling/recyclization of 2-(2-bromoaryl)cyclopropane-1,1-dicarboxylates with primary nitro alkanes
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The first successful synthesis of 1H-2,3-benzoxazine 3-oxides has been described. The efficiency of the approach is provided by the C-C-coupling of 2-(2-bromoaryl)cyclopropane-1,1-dicarboxylates with primary nitroalkanes catalyzed by Pd(dba)2/JohnPhos system followed by in situ recyclization of the intermediates. Several representative transformations allowing selective modification of the nitronate as well as malonate functionalities in the resulting compounds are demonstrated.
- Mikhaylov, Andrey A.,Dilman, Alexander D.,Novikov, Roman A.,Khoroshutina, Yulia A.,Struchkova, Marina I.,Arkhipov, Dmitry E.,Nelyubina, Yulia V.,Tabolin, Andrey A.,Ioffe, Sema L.
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supporting information
p. 11 - 14
(2015/12/23)
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- Versatile synthesis of isoquinolines and isochromenes by Pd-catalyzed oxidative carbonylation of (2-alkynyl)benzylideneamine derivatives
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Isoquinoline-4-carboxylic esters 3 and isochromene-4-carboxylic esters 4 have been conveniently prepared by direct PdI2-catalyzed oxidative heterocyclization/alkoxycarbonylation of readily available (2- alkynylbenzylidene)amine derivatives. In particular, (2-alkynylbenzylidene) (tert-butyl)amines 2 selectively afforded isoquinoline derivatives 3 by N-cyclization, whereas N-(2-alkynylbenzylidene)-N′-phenylhydrazines 5 led to the formation of isochromenes 4 through O-cyclization ensuing from water attack on the imino group of the substrate. Reactions were carried out in alcoholic solvents at 80-100 °C and under 20-80 atm (at 25 °C) of a 4:1 mixture of CO/air, in the presence of PdI2 (2-10 mol-%) in conjunction with KI (KI/PdI2 molar ratio = 10). In the case of imines 2, the use of a dehydration agent, such as trialkyl orthoformate, was necessary to obtain satisfactory yields of isoquinolines 3.
- Gabriele, Bartolo,Veltri, Lucia,Maltese, Vito,Spina, Rosella,Mancuso, Raffaella,Salerno, Giuseppe
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experimental part
p. 5626 - 5635
(2011/11/29)
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- AROMATIC SULFONE COMPOUND AS ALDOSTERONE RECEPTOR MODULATOR
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The present invention provides a compound represented by the following formula (I): [wherein, A represents a group of the following formula (A-1): etc., R1 and R2 each independently represent a hydrogen atom etc., Z represents CR3 etc., W represents CR4 etc., Q represents CR5 etc., R3, R4 and R5 each independently represent a hydrogen atom etc., Y represents an oxygen atom or sulfur atom, X represents an oxygen atom etc. and B represents an optionally substituted aryl group or optionally substituted heteroaryl group], the prodrug thereof or the pharmaceutically acceptable salt thereof for preventing or treating various diseases such as hypertesion, cerebral stroke, cardiac failure, etc.
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Page/Page column 39
(2010/11/28)
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