On February 27, 2020, Crew, Andrew P.; Dong, Hanqing; Berlin, Michael; Sparks, Steven M. published a patent.Category: esters-buliding-blocks The title of the patent was Preparation of proteolysis targeting chimeric (PROTAC) compounds with E3 ubiquitin ligase binding activity and targeting α-synuclein protein for treating neurodegenerative diseases. And the patent contained the following:
The present disclosure relates to bifunctional compounds, which find utility as modulators of α-synuclein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, inhibitors of apoptosis proteins or mouse double-minute homolog 2 ligand which binds to the resp. E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. A bifunctional compounds I [ULM-L-PTM; wherein the ULM = a small mol. E3 ubiquitin ligase binding moiety; the PTM = a small mol. comprising a α-synuclein protein targeting moiety; and the L = a bond or a chem. linking moiety connecting the ULM and the PTM] or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or prodrugs thereof, were disclosed. E.g., a multi-step synthesis of II, starting from 2-(2-benzyloxyethoxy)ethanol and tert-Bu 2-bromoacetate, was described. Targeted degradation of sarkosyl insoluble (SI) α-synuclein via exemplary bifunctional compounds I was assessed by MJFF-14-6-4-2 conformation specific ELISA following treatment of PFF-induced A53T α-synuclein overexpressing HEK293 cells with 1μM exemplary compound compared to DMSO vehicle control (data given for representative compounds I). Diseases or disorders that result from aggregation or accumulation of the target protein are α-synucleinopathies or neurodegenerative diseases associated with α-synuclein accumulation and aggregation, such as e.g., Parkinson disease, Alzheimer’s disease, dementia, dementia with Lewy bodies or multiple system atrophy, in particular Parkinson’s disease. The experimental process involved the reaction of tert-Butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate(cas: 882518-89-0).Category: esters-buliding-blocks
The Article related to proteolysis targeting chimeric protac bifunctional compound preparation protein degradation, sarkosyl insoluble alpha synuclein targeted degradation bifunctional compound preparation, alpha synucleinopathy neurodegenerative disease treatment bifunctional compound preparation and other aspects.Category: esters-buliding-blocks
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