Tau-protein targeting protacs and associated methods of use
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A technique for selecting, chemical structures, applied in the field of bifunctional compounds
Pending Publication Date: 2019-09-13
ARVINAS
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[0017] Tau aggregation inhibitors confirming promising preclinical data have proven ineffective in recent clinical trials for the treatment of various tauopathies
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[0761] PROTAC compounds of the present disclosure are effective in Tau degradation. Exemplary compounds are presented in Tables 1 and 2, with in vitro data for some selected compounds in Tables 2 and 3 showing degradation of tau protein. In vivo studies showing tau protein degradation in figure 1 shown in .
[0762] General Methods of Chemical Synthesis
[0763]Synthesis of the claimed chimeric compounds can be carried out according to general synthetic procedures known in the literature. The synthetic routes shown in the schemes in this disclosure are described as one of the methods that can be used to obtain the desired compounds. Other methods may also be useful to those skilled in the synthetic arts. The ULM and PTM described in the scheme represent only one of many ULMs and PTMs in this patent application.
[0764] LC-MS Method for Purity Analysis (Quality Control)
[2376] One aspect of the present disclosure provides bifunctional compounds having the following chemical structures:
[2377] ULM-L-PTM,
[2378] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,
[2379] in:
[2380] The ULM is a small molecule E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase;
[2381] The PTM is a Tau protein targeting moiety; and
[2382] Said L is a bond or a chemical linkage moiety linking ULM and PTM.
[2383] In any aspect or embodiment described herein, the E3 ubiquitin ligase binding moiety targets an E3 ubiquitin ligase selected from VonHippel-Lindau (VLM) and cereblon (CLM).
[2384] In any aspect or embodiment described herein, the PTM is represented by Formula I, II, III, IV, V, VI, VII, VIII, IX, X or XI:
[2385]
[2386] in:
[2387] A, B, C, D, E and F are independently selected from an optionally substituted 5 or 6 membered aryl or heteroaryl ring, an optionally ...
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Abstract
The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain onone end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase toeffect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation / inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
Description
[0001] Cross References to Related Applications [0002] This disclosure claims priority to US Provisional Application No. 62 / 415,830, filed November 1, 2016, which is hereby incorporated by reference in its entirety. [0003] incorporated by reference [0004] U.S. Patent Application Serial No. 15 / 230,354, filed August 5, 2016; and U.S. Patent Application Serial No. 62 / 406,888, filed October 11, 2016; and published as U.S. Patent Application Publication No. 2015 / 0291562, U.S. Patent Application Serial No. 14 / 686,640, filed April 14, 2015; and U.S. Patent Application Serial No. 14 / 792,414, filed July 6, 2015, published as U.S. Patent Application Publication No. 2016 / 0058872; and U.S. Patent Application Serial No. 14 / 371,956, filed July 11, 2014, published as U.S. Patent Application Publication No. 2014 / 0356322; and published as U.S. Patent Application Publication No. 2016 / 0272639, filed March 18, 2016 Filed US Patent Application Serial No. 15 / 074,820, which is hereby incorp...
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