220514-28-3Relevant articles and documents
X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
, p. 8303 - 8332 (2021/06/30)
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
SKLB1039 Compound as well as preparation method and application thereof
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, (2021/10/27)
The invention belongs to the technical field of preparation of new compounds, and particularly relates SKLB1039 compound as well as a preparation method and application thereof. The 2 -methyl -3 -nitrobenzoic acid is taken as an initial raw material and is brominated. Esterification, reduction, reductive amination and hydrolysis synthesis 5 - bromo -2 - methyl -3 - (N - ethyl, N - (tetrahydropyran -4 - yl)) aminobenzoic acid. The cyclohexanone serving as a raw material is subjected to catalytic hydrogenation reduction of carbonyl α, acetyl cyclohexanone and cyanopyridone to synthesize 4 - aminomethyl -1 - methyl -5, 6, 7, 8 - tetrahydroisoquinoline -3 (2H) - ketone. Coupling the two to an amide is followed by catalytic coupling with an aryl sheet to give SKLB1039 a compound. SKLB1039 Large-scale preparation technology is provided, operation is easy, the post-treatment purification process is simple, the total route yield is improved, raw materials are easy to purchase, the price is low, and the production cost is greatly reduced.
Synthesis and evaluation of a novel series of 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylic acid-substituted amide derivatives as anticancer, antiangiogenic, and antioxidant agents
Sawant, Ajay S.,Kamble, Sonali S.,Pisal, Parshuram M.,Meshram, Rohan J.,Sawant, Sanjay S.,Kamble, Vilas A.,Kamble, Vinod T.,Gacche, Rajesh N.
, p. 17 - 32 (2019/11/14)
A series of novel indazole derivatives has been synthesized and evaluated for anticancer, antiangiogenic, and antioxidant activities. The capability of the synthesized compounds 11a–x to hinder the viability of three human cancer cells lines, HEP3BPN 11 (liver), MDA 453 (breast), and HL 60 (leukemia), were assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Among the compounds 11a–x screened, 11c and 11d showed the higher inhibitory activity on the viability of HEP3BPN 11 (liver), when compared with the standard methotrexate. These compounds were further tested to evaluate their potential to inhibit the proangiogenic cytokines associated with tumor development. Compound 11c was found to be a potent antiangiogenic agent against TNFα, VEGF, and EGF, whereas 11d showed potent antiangiogenic activity against TNFα, VEGF, IGF1, TGFb, and leptin inhibition. All the compounds 11a–x were screened for their antioxidant activities using 2,2-diphenyl-1-picryl hydrazine (DPPH), hydroxyl (OH), and superoxide radical (SOR) scavenging activity. Compounds 11n, 11p, 11q, and 11v have shown significant OH radical scavenging activities, also compounds 11c, 11h, and 11k were found to have a DPPH radical scavenging activity and compounds 11a and 11m exhibited better SOR scavenging activity when compared with the reference compound ascorbic acid. In silico molecular docking analysis revealed important structural insights behind observed anti TNFα effect by present indazole compounds.
Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors
Feng, Qiang,Feng, Zhanzhan,He, Hualong,Hu, Xi,Liu, Zhihao,Teng, Fei,Yu, Luoting,Zhang, Qiangsheng
, (2020/01/22)
Enhancer of zeste homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repression complex 2 (PRC2), which is implicated in cancer progression metastasis and poor prognosis. Based on our EZH2 inhibitor SKLB1049 with low nanomolar activity, we e
SELECTIVE INHIBITORS OF CLINICALLY IMPORTANT MUTANTS OF THE EGFR TYROSINE KINASE
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Page/Page column 146, (2019/01/21)
The present invention provides compounds of Formula (I) or a subgeneric structure or species thereof, or a pharmaceutically acceptable salt, ester, solvate, and/or prodrug thereof, and methods and compositions for treating or ameliorating abnormal cell pr
EZH2 Inhibitors
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Paragraph 0318-0321, (2018/11/02)
The present invention relates to compounds that inhibit EZH2 activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention.
COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ENHANCER OF ZESTE HOMOLOG 2 POLYPEPTIDE
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Paragraph 1235-1239, (2018/07/15)
The present disclosure relates to bifunctional compounds, which find utility as modulators of enhancer of zeste homolog 2 (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective 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. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
HETEROCYCLIC COMPOUNDS AS INHIBITORS OF RAS AND METHODS OF USE THEREOF
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Page/Page column 128, (2018/04/21)
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, B, R", Q, W, X, Y, Z, n1, n2and '--" are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also disclosed.
MDM2-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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Paragraph 0422; 0424, (2017/01/31)
The description relates to MDM2 binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the MDM2 E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
Dihydrothiazolone compounds containing sulfamide and pharmaceutical compositions and use thereof
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Paragraph 0198; 0199; 0200; 0204, (2016/10/08)
The invention provides dihydrothiazolone compounds containing sulfamide, represented by a formula (I), pharmaceutical compositions and use thereof. The compounds can be combined with proteins with bromodomain structural domains so as to adjust a downstream signal channel and exert a special function, and can be used for treating many diseases associated with bromodomain structural domains. The compounds can interfere combination of Brd4 with the bromodomain structural domain and an acetylized histone so as to down-regulate transcription of a cancer gene c-myc and associated target genes thereof, so that the compounds can become effective therapeutic drugs for treating tumors.