58584-83-1Relevant articles and documents
BICYCLIC COMPOUND AND USE THEREOF
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Paragraph 0548-0549, (2021/04/10)
The present disclosure relates to a compound derivative containing a 6-7 bicyclic ring and use thereof. The compound according to the present invention can be effectively used in the prevention or treatment of diseases caused by PRMT5 by acting as a PRMT5 inhibitor.
Synthesis of novel pyridine and pyrimidine derivatives as potential inhibitors of HIV-1 reverse transcriptase using palladium-catalysed C-N cross-coupling and nucleophilic aromatic substitution reactions
Changunda, Charles R.K.,Rousseau, Amanda L.,Basson, Adriaan E.,Bode, Moira L.
, p. 152 - 170 (2021/05/27)
Palladium-mediated cross-coupling reactions are used in the successful construction of a small library of flexible heteroatom-linked diarylpyridine target compounds, including pyridines bearing a secondary amide substituent. Heteroatom-linked diarylpyrimidine derivatives bearing a chlorine substituent are prepared by base-catalysed nucleophilic aromatic substitution reactions without the need for palladium catalysis.
Gut-Restricted Selective Cyclooxygenase-2 (COX-2) Inhibitors for Chemoprevention of Colorectal Cancer
Zhang, Zhuming,Ghosh, Avijit,Connolly, Peter J.,King, Peter,Wilde, Thomas,Wang, Jianyao,Dong, Yawei,Li, Xueliang,Liao, Daohong,Chen, Hao,Tian, Gaochao,Suarez, Javier,Bonnette, William G.,Pande, Vineet,Diloreto, Karen A.,Shi, Yifan,Patel, Shefali,Pietrak, Beth,Szewczuk, Lawrence,Sensenhauser, Carlo,Dallas, Shannon,Edwards, James P.,Bachman, Kurtis E.,Evans, David C.
, p. 11570 - 11596 (2021/07/31)
Selective cyclooxygenase (COX)-2 inhibitors have been extensively studied for colorectal cancer (CRC) chemoprevention. Celecoxib has been reported to reduce the incidence of colorectal adenomas and CRC but is also associated with an increased risk of cardiovascular events. Here, we report a series of gut-restricted, selective COX-2 inhibitors characterized by high colonic exposure and minimized systemic exposure. By establishing acute ex vivo 18F-FDG uptake attenuation as an efficacy proxy, we identified a subset of analogues that demonstrated statistically significant in vivo dose-dependent inhibition of adenoma progression and survival extension in an APCmin/+ mouse model. However, in vitro-in vivo correlation analysis showed their chemoprotective effects were driven by residual systemic COX-2 inhibition, rationalizing their less than expected efficacies and highlighting the challenges associated with COX-2-mediated CRC disease chemoprevention.
HETEROARYL AMIDES USEFUL AS KIF18A INHIBITORS
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Paragraph 0251-0252, (2020/07/14)
The present invention relates to chemical compounds having a general formula (I), as defined herein, and synthetic intermediates thereof, which are capable of modulating KIF18A protein thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of KIF18A.
Discovery of [1,2,4]triazolo[4,3-a]pyridines as potent Smoothened inhibitors targeting the Hedgehog pathway with improved antitumor activity in vivo
Chen, Mian,Lv, Lin,Quan, Dongling,Schmitz, John C.,Tian, Nannan,Tian, Yuanxin,Wei, Ning,Wu, Huanxian,Wu, Shaoyu,Xie, Ying,Xu, Yimei,Yang, Danni,Yang, Zichao,Zhang, Huiwu,Zhang, Jiajie,Zhang, Tingting,Zhou, Lei
, (2020/07/03)
Triple-negative breast cancer (TNBC), a subset of breast cancers, have poorer survival than other breast cancer types. Recent studies have demonstrated that the abnormal Hedgehog (Hh) pathway is activated in TNBC and that these treatment-resistant cancers are sensitive to inhibition of the Hh pathway. Smoothened (Smo) protein is a vital constituent in Hh signaling and an attractive drug target. Vismodegib (VIS) is one of the most widely studied Smo inhibitors. But the clinical application of Smo inhibitors is limited to adult patients with BCC and AML, with many side effects. Therefore, it's necessary to develop novel Smo inhibitor with better profiles. Twenty [1,2,4]triazolo[4,3-a]pyridines were designed, synthesized and screened as Smo inhibitors. Four of these novel compounds showed directly bound to Smo protein with stronger binding affinity than VIS. The new compounds showed broad anti-proliferative activity against cancer cell lines in vitro, especially triple-negative breast cancer cells. Mechanistic studies demonstrated that TPB15 markedly induced cell cycle arrest and apoptosis in MDA-MB-468 cells. TPB15 blocked Smo translocation into the cilia and reduced Smo protein and mRNA expression. Furthermore, the expression of the downstream regulatory factor glioma-associated oncogene 1 (Gli1) was significantly inhibited. Finally, TPB15 demonstrated greater anti-tumor activity in our animal models than VIS with lower toxicity. Hence, these results support further optimization of this novel scaffold to develop improved Smo antagonists.
Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents
Liu, Lingfeng,Kong, Chengcheng,Fumagalli, Marco,Savková, Karin,Xu, Yiwen,Huszár, Stanislav,Sammartino, José C.,Fan, Dongguang,Chiarelli, Laurent R.,Miku?ová, Katarína,Sun, Zhaogang,Qiao, Chunhua
, (2020/09/09)
Decaprenylphosphoryl-β-D-ribose 2′-oxidoreductase (DprE1) is a promising drug target for the development of novel anti-tubercular agents, and inhibitors of DprE1 are being investigated extensively. Among them, the 1,3-benzothiazinone compounds such as BTZ
Synthesis and in vitro antitumor activity of novel naphthyridinone derivatives
Jia, Xue-Dong,Wang, Shuo,Wang, Ming-Hua,Liu, Ming-Liang,Xia, Gui-Min,Liu, Xiu-Jun,Chai, Yun,He, Hong-Wei
supporting information, p. 235 - 239 (2017/01/28)
A series of naphthyridinone derivatives based on 1a (a precursor of Voreloxin) were designed and synthesized. Seven compounds having >70% inhibition against HL60 at 30 μmol/L were further evaluated for their in vitro antitumor activity by SRB assay. Results reveal that thiazol-2-yl and 3-aminomethyl-4-benzyloxyimino-3-methylpyrrolidin-1-yl groups are optimal at the N-1 and C-7 positions of naphthyridinone core, respectively. 10j exhibits broad-spectrum activity (IC50: 100-fold more potent than the two references against eight of these cell lines.
Discovery of a potent, selective, and orally bioavailable acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor: Discovery of 2-[(3 s)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]- 3-piperidyl]acetic acid (AZD4017)
Scott, James S.,Bowker, Suzanne S.,Deschoolmeester, Joanne,Gerhardt, Stefan,Hargreaves, David,Kilgour, Elaine,Lloyd, Adele,Mayers, Rachel M.,McCoull, William,Newcombe, Nicholas J.,Ogg, Derek,Packer, Martin J.,Rees, Amanda,Revill, John,Schofield, Paul,Selmi, Nidhal,Swales, John G.,Whittamore, Paul R. O.
supporting information; experimental part, p. 5951 - 5964 (2012/08/07)
Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11β-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.
Discovery of CX-5461, the first direct and selective inhibitor of RNA polymerase I, for cancer therapeutics
Haddach, Mustapha,Schwaebe, Michael K.,Michaux, Jerome,Nagasawa, Johnny,O'Brien, Sean E.,Whitten, Jeffrey P.,Pierre, Fabrice,Kerdoncuff, Pauline,Darjania, Levan,Stansfield, Ryan,Drygin, Denis,Anderes, Kenna,Proffitt, Chris,Bliesath, Josh,Siddiqui-Jain, Adam,Omori, May,Huser, Nanni,Rice, William G.,Ryckman, David M.
supporting information; experimental part, p. 602 - 606 (2012/10/08)
Accelerated proliferation of solid tumor and hematologic cancer cells is linked to accelerated transcription of rDNA by the RNA polymerase I (Pol I) enzyme to produce elevated levels of rRNA (rRNA). Indeed, upregulation of Pol I, frequently caused by mutational alterations among tumor suppressors and oncogenes, is required for maintenance of the cancer phenotype and forms the basis for seeking selective inhibitors of Pol I as anticancer therapeutics. 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c] fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (CX-5461, 7c) has been identified as the first potent, selective, and orally bioavailable inhibitor of RNA Pol I transcription with in vivo activity in tumor growth efficacy models. The preclinical data support the development of CX-5461 as an anticancer drug with potential for activity in several types of cancer.
Effects of the pyridine 3-substituent on regioselectivity in the nucleophilic aromatic substitution reaction of 3-substituted 2,6-dichloropyridines with 1-methylpiperazine studied by a chemical design strategy
Bach, Peter,Marczynke, Michaela,Giordanetto, Fabrizio
, p. 6940 - 6952 (2013/02/22)
A chemical design strategy has been used to select 3-substituted 2,6-dichloropyridines for the nucleophilic aromatic substitution reaction with 1-methylpiperazine. The aim was to study the dependency of the regioselectivity in these reactions on the character of the pyridine 3-substituent expressed by their lipophilicity (PI), size (MR), and inductive effect (Ip). Interestingly, the regioselectivity did not correlate with any of these parameters, but in a statistically significant manner with the Verloop steric parameter B1, as indicated by the p value of 0.006 (R2 = 0.45). This implies that bulky 3-substituents close to the pyridine ring induce regioselectivity towards the 6-position. Useful in practical synthesis is the different regioselectivity obtained with a carboxylic acid 3-substituent and precursors or derivatives thereof. Thus, in acetonitrile as solvent, 3-carboxylate and 3-amide substituents were preferred to obtain the 2-isomer (9:1 ratio of the 6-isomer), whereas the 3-cyano and 3-trifluoromethyl substitutents were preferred to obtain the 6-isomer (9:1 ratio of the 2-isomer). Analysis of the regioselectivity Rsel for the pyridine 2-position in the reaction of 2,6-dichloro-3-(methoxycarbonyl)pyridine with 1-methylpiperazine in 21 different solvents showed that Rsel could be predicted by the Kamlet-Taft equation: Rsel = 1.28990 + 0.03992α - 0.59417β - 0.46169π* (R2 = 0.95, p = 1.9 × 10-10). Rsel is thus mainly correlated with the ability of the solvent to function as a hydrogen-bond acceptor, as expressed by the solvatochromic β parameter. Thus, the 16:1 regioselectivity for the 2-isomer in DCM (β = 0.10) could be switched to a 2:1 selectivity for the 6-isomer in DMSO (β = 0.76). Copyright
