- Compound for targeted ubiquitination degradation of ERRalpha protein and pharmaceutical composition and application thereof
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The invention provides a compound with a structure shown as a formula (I), which has the effects of inhibiting ERRalpha protein activity and degrading ERRalpha protein activity, has relatively strongsubtype selectivity and can also effectively inhibit tri
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Paragraph 0234-0235; 0239-0241
(2020/06/20)
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- Identification of New Small-Molecule Inducers of Estrogen-related Receptor α (ERRα) Degradation
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A series of (E)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxyphenyl)-2-cyanoacrylamide derivatives were designed and synthesized as new estrogen-related receptor α (ERRα) degraders based on the proteolysis targeting chimera (PROTAC) concept. One of the representative compounds 6c is capable of specifically degrading ERRα protein by >80% at a relatively low concentration of 30 nM, becoming one of the most potent and selective ERRα degraders to date. Compound 6c could be utilized as a new powerful research tool for further biological investigation of ERRα.
- Peng, Lijie,Zhang, Zhensheng,Lei, Chong,Li, Shan,Zhang, Zhang,Ren, Xiaomei,Chang, Yu,Zhang, Yan,Xu, Yong,Ding, Ke
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supporting information
p. 767 - 772
(2019/05/08)
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- Preparation method for beta-alanine t-butyl ester hydrochloride
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The present invention discloses a preparation method for beta-alanine t-butyl ester hydrochloride. The method comprises the following steps of dissolving tert-butyl cyanoacetate in a solvent, adding an alkali into the solvent, then using Raney nickel to carry out catalytic hydrogenation, and after hydrogenation, removing the catalyst through filtration and obtaining a hydrogenated product after concentration; and dissolving the hydrogenated product into an organic solvent, dropwise adding an organic solvent of hydrogen chloride, and after the pH reaches 2-3, carrying out concentrating and drying under reduced pressure to obtain a target product. According to the method disclosed by the present invention, amino acid derivatives are prepared by using the catalytic hydrogenation, and the product is good in quality and high in yield; requirements on devices and reaction conditions are low, operations are simple, and the reaction conditions are mild, so that the method is suitable for industrial large-scaled production; and raw materials and reagents used are easily available and low in price, so that the product cost is low.
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Paragraph 0022; 0023
(2016/10/10)
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- Synthesis and structure of a bis-glycosylated hexa-β-peptide
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The bis-glycosylated hexapeptide β-Ala-β-Ala-(β-D-Glc)-L- Asp-β-Ala-β-Ala-(β-D-Gal)-L-Asp (14) is prepared by fragment condensation of Fmoc-β-Ala-β-Ala-(β-D-GlcAc4)-L-Asp-OH (11) and H2N-β-Ala-β-Ala-(β-D-GalAc4)-L-Asp-OtBu (12) under optimized conditions
- Daiber, Ralf,Ziegler, Thomas
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p. 408 - 420
(2013/04/10)
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- N-2-(2-PYRIDINYL)-4-PYRIMIDINYL-BETA-ALANINE DERIVATIVES AS INHIBITORS OF HISTONE DEMETHYLASE JMJD3
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A method of treating autoimmune diseases or conditions in a mammal, such as a human, which comprises the administration of a therapeutically effective amount of histone demethylase enzymes of formula (I).
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Page/Page column 80
(2012/05/05)
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- Preparation of new 1,4-diazocanes as scaffolds for combinatorial chemistry
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Hexahydro-2-oxo-1,4-diazocin-6-carboxylic acid constitutes a conformationally rigid, crown-shaped scaffold. An orthogonally protected (Boc at N-4 and methyl ester at 6-CO2H) representative was prepared by ring expansion of a 3-pyrrolidone-derived 1,4-diketone with MeNH2. After deprotection, this building block was further diversified by reductive aminations and amidations and by sulfonamide and urea formation. Furthermore, the 6-CO2H function was transformed into a 6-NHCbz group in one step by carboxamide degradation in the presence of BnOH. An example of a cyclic tripeptoidic structure was synthesized by amidation with N-Boc-β-alanine and glycine methyl ester. Structural features of the eight-membered heterocycle were established by single-crystal X-ray structure analysis of a 4-bromoaniline derivative.
- Penning, Miriam,Christoffers, Jens
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experimental part
p. 1809 - 1818
(2012/05/04)
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- Synthesis and self-association properties of flexible guanidiniocarbonylpyrrole-carboxylate zwitterions in DMSO: Intra- versus intermolecular ion pairing
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(Chemical Equation Presented) We have synthesized a new class of flexible zwitterions 6a-e, in which a carboxylate is linked via an alkyl chain with variable length (one to five methylene groups) to a guanidiniocarbonylpyrrole cation. The self-association properties of these zwitterions were determined by NMR dilution studies in DMSO and by ESI-MS experiments. The stability and hence also the size of the aggregates formed via self-assembly is critically dependent on the length and therefore flexibility of the spacer. Whereas the smallest zwitterion 6a forms large aggregates already at low concentrations, the more flexible zwitterions only form small oligomers (6b) or dimers (6c-e) at much larger concentrations. The differences between the five zwitterions can be explained based on the different extent of intramolecular ion pairing within the monomers. Any intramolecular ion pairing, which becomes possible with increasing linker length, stabilizes the monomer and therefore destabilizes any oligomer.
- Schmuck, Carsten,Rehm, Thomas,Geiger, Lars,Schaefer, Mathias
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p. 6162 - 6170
(2008/02/10)
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- HETEROCYCLIC METHYL SULFONE DERIVATIVE
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Provided is a compound capable of inhibiting production or secretion of β amyloid protein. A compound represented by the following formula (1): (wherein, R1 represents a heterocyclic group which may have a substituent, R2 represents a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, R3 represents a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, R4 represents a hydrogen atom or a C1-6 alkyl group, and X represents -S-,-SO- or -SO2-) an N-oxide or S-oxide thereof; a salt thereof; or a solvate thereof; and a medicament containing any of them.
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Page/Page column 115
(2010/11/08)
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- Thrombopoietin mimetics
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Invented are non-peptide TPO mimetics. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a selected substituted naphthimidazole derivative.
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- Building Units for N-Backbone Cyclic Peptides. 3. Synthesis of Protected Nα-(ω-Aminoalkyl)amino Acids and Nα-(ω-Carboxyalkyl)amino Acids
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An improved synthesis of a family of amino acids that contain ω-aminoalkyl groups and of a new family containing ω-carboxyalkyl groups linked to the α-amine is described. The synthesis was performed by alkylation of suitably monoprotected alkylenediamines and protected ω-amino acids with triflates of α-hydroxy acid esters. The reaction proceeded with inversion of configuration yielding optically pure products. The Nα-(ω-aminoalkyl)amino acids and Nα-(ω-carboxyalkyl)amino acids were orthogonally protected to allow their incorporation into peptides by solid-phase peptide synthesis (SPPS) methodology.
- Muller, Dan,Zeltser, Irena,Bitan, Gal,Gilon, Chaim
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p. 411 - 416
(2007/10/03)
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- Synthesis of Organothiophosphate Antigens for the Development of Specific Immunoassays
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By use of t-butyl 3-propanoate (1), a general method was developed that allowed the preparation of analogues of specific organothiophosphates; these analogues are suitable for use as haptens in the development of tests for detection of the individual organophosphates.The bifunctional reagent (1) was conveniently prepared from readily available starting materials.
- McAdam, David P.,Skerritt, John H.
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p. 959 - 967
(2007/10/02)
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- New kelatorphan-related inhibitors of enkephalin metabolism: Improved antinociceptive properties
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In order to improve the in vivo protection of enkephalins from enzymatic degradation, a new series of inhibitors derived from kelatorphan [HONHCOCH2CH(CH2Ph)CONHCH(CH3)COOH], the first-described complete inhibitor of enkephalin metabolism, were designed by modification of the C-terminal amino acid. The progressive lengthening of the chain of this residue shows that a β-alanine seems to be the best basic model for the conception of such types of compounds. On the other hand, the methylation of the amide bond, which is well accepted by aminopeptidase N (EC 3.4.11.2) and dipeptidylaminopeptidase, induced a significant loss of affinity for neutral endopeptidase -24.11. Starting from these data, compounds containing a variously substituted β-alanine residue and corresponding to the general formula HONHCOCH2CH(CH2Ph)CONHCH(R1)CH(R2)COOH were synthesized. All these molecules inhibit neutral endopeptidase -24.11 and dipeptidylaminopeptidase in the nanomolar range, and those containing an aromatic chain (compound 7A, R1 = CH2Ph,R2 = H, and compound 8A, R1 = Ph, R2 = H) inhibit the biologically relevant aminopeptidase N, with IC50's around 10-8 M. Intracerebroventricular injection in mice of these multienzyme inhibitors produced an efficient and naloxone-reversible analgesic response (hot plate test): compounds 7A and 8A were shown to be more potent than kelatorpohan in increasing the jump latency time, in agreement with their in vitro properties, and these new compounds were found to increase the forepaw lick latency, a reflex considered as a typical morphine response.
- Xie,Soleilhac,Schmidt,Peyroux,Roques,Fournie-Zaluski
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p. 1497 - 1503
(2007/10/02)
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