- Synthesis of novel 7-azaindole derivatives containing pyridin-3-ylmethyl dithiocarbamate moiety as potent PKM2 activators and PKM2 nucleus translocation inhibitors
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Multiple lines of evidence have indicated that pyruvate kinase M2 (PKM2) is upregulated in most cancer cells and it is increasingly recognized as a potential therapeutic target in oncology. In a continuation of our discovery of lead compound 5 and SAR study, the 7-azaindole moiety in compound 5 was systematically optimized. The results showed that compound 6f, which has a difluoroethyl substitution on the 7-azaindole ring, exhibited high PKM2 activation potency and anti-proliferation activities on A375 cell lines. In a xenograft mouse model, oral administration of compound 6f led to significant tumor regression without obvious toxicity. Further mechanistic studies revealed that 6f could influence the translocation of PKM2 into nucleus, as well as induction of apoptosis and autophagy of A375 cells. More importantly, compound 6f significantly inhibited migration of A375 cells in a concentration-dependent manner. Collectively, 6f may serve as a lead compound in the development of potent PKM2 activators for cancer therapy.
- Liu, Bin,Yuan, Xia,Xu, Bo,Zhang, Han,Li, Ridong,Wang, Xin,Ge, Zemei,Li, Runtao
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- Design and Synthesis of Potent and Selective PIM Kinase Inhibitors by Targeting Unique Structure of ATP-Binding Pocket
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In the development of kinase inhibitors, one of the major concerns is selectivity. An effective strategy to achieve high selectivity is to utilize structural differences among kinases to inform inhibitor design. Here, we set out to improve the PIM (proviral integration site for Moloney murine leukemia virus) kinase-inhibitory selectivity of our previously reported 7-azaindole derivative 2, which has promising ADMET properties, by targeting a unique bulge in the ATP-binding pocket. 6-Substituted 7-azaindoles, especially the 6-chlorinated derivatives, proved to be potent and selective PIM kinase inhibitors and appear to be promising lead compounds for future drug discovery.
- Nakano, Hirofumi,Hasegawa, Tsukasa,Kojima, Hirotatsu,Okabe, Takayoshi,Nagano, Tetsuo
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supporting information
p. 504 - 509
(2017/05/19)
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- Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: Lead optimization
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Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.
- Alonso, Juan Antonio,Andrs, Miriam,Bravo, Mnica,Calbet, Marta,Eastwood, Paul R.,Eichhorn, Peter,Esteve, Cristina,Ferrer, Manel,Gmez, Elena,Gonzlez, Jacob,Mir, Marta,Moreno, Imma,Petit, Silvia,Roberts, Richard S.,Sevilla, Sara,Vidal, Bernat,Vidal, Laura,Vilaseca, Pere,Zanuy, Miriam
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p. 5123 - 5126
(2015/01/08)
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- NEW CRTH2 ANTAGONISTS
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The present invention relates to compounds of formula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by CRTh2 antagonist activity.
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- New CRTh2 antagonists
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The present invention relates to compounds of formula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by CRTh2 antagonist activity.
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Paragraph 0442-0445
(2013/03/26)
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- ANTICANCER AGENT
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An anticancer agent comprising a compound represented by the formula (I) [R1 represents hydrogen atom, hydroxyl group, a C1-6alkoxy group and the like; R2 and R3 represents hydrogen atom, a halogen atom, a C1-6alkyl group and the like; R4 represents hydrogen atom, a C1-6alkyl group, a C1-6alkylsulfonyl group and the like; R5 represents hydrogen atom or a substituent; .... represents a single bond or a double bond; R6 and R7 represents hydrogen atom, a C1-6alkyl group and the like; R8 represents hydrogen atom, a C1-6alkyl group and the like; A represents -O-, -S-, or - CH2-; D represents -C= or -N=; X represents methylene group, -O-, or -CO-; Q represents -N= or -C(R8)=; and Y represents a heterocyclic group or amino group], which shows a superior inhibitory activity against pim-1 kinase.
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Paragraph 0289
(2013/03/26)
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- Scaffold-hopping strategy: Synthesis and biological evaluation of 5,6-fused bicyclic heteroaromatics to identify orally bioavailable anticancer agents
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Utilizing scaffold-hopping drug-design strategy, we sought to identify a backup drug candidate for BPR0L075 (1), an indole-based anticancer agent. For this purpose, 5,6-fused bicyclic heteroaromatic scaffolds were designed and synthesized through shufflin
- Tung, Yen-Shih,Coumar, Mohane Selvaraj,Wu, Yu-Shan,Shiao, Hui-Yi,Chang, Jang-Yang,Liou, Jing-Ping,Shukla, Paritosh,Chang, Chun-Wei,Chang, Chi-Yen,Kuo, Ching-Chuan,Yeh, Teng-Kuang,Lin, Chin-Yu,Wu, Jian-Sung,Wu, Su-Ying,Liao, Chun-Chen,Hsieh, Hsing-Pang
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p. 3076 - 3080
(2011/06/25)
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- Discovery of [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl] acetic acids as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications
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Efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl] acetic acid aldose reductase inhibitors. The lead candidate, [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyri din-1-yl]acetic acid example 16, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50 > 100 μM), a related enzyme involved in the detoxification of reactive aldehydes.
- Van Zandt, Michael C.,Doan, Brian,Sawicki, Diane R.,Sredy, Janet,Podjarny, Alberto D.
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supporting information; experimental part
p. 2006 - 2008
(2009/11/30)
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- Anti-tumor compounds
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Compounds of the following formula: wherein A, D, Q, T, U, V, W, X, Y, Z, R1, and ---- are as defined herein. This invention also relates to a method of inhibiting tubulin polymerization, or treating cancer or an angiogenesis-related disorder w
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Page/Page column 11
(2008/06/13)
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- The synthesis of 4-benzylamino-6-methyl-1H-pyrrolo[3,2-c]pyridine and 4-benzylamino-6-methyl- 1H-pyrrolo[2,3-b]pyridine
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4-Benzylamino-6-methyl-1H-pyrrolo[3,2-c]pyridine (2) and 4-benzylamino-6-methyl-1H-pyrrolo[2,3-b]pyridine (3) were synthesized as deaza analogues of the anxiolytic agent 4-benzylamino-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (1). The 1-deaza analogue (2) was
- Meade, Eric A.,Beauchamp, Lilia M.
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p. 303 - 308
(2007/10/03)
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- Synthesis of Pyrrolopyridines (Azaindoles)
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Improved, convenient, and reliable routes for synthesis of 4-,5-,6-, and 7-azaindole, 7-methyl-4-azaindole, 7-methyl-6-azaindole, and the hithero unreported 7-amino-4-azaindole are described.The syntheses have been accomplished either by significant modifications to established procedures or by new methods with afford the compounds in improved yields.
- Mahadevan,Indumathy,Rasmussen, Malcolm
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p. 359 - 367
(2007/10/02)
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