959961-65-0Relevant academic research and scientific papers
Bromine structural domain inhibitor compound and application thereof
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Paragraph 0217-0220, (2019/08/02)
The invention relates to a bromine structural domain inhibitor and provides a compound shown in a general formula I, pharmaceutical salt, an enantiomer, a diastereoisomer, an atropisomer, racemate, apolymorphic substance and solvate of the compound or an isotope labelled compound (including a deuterium substituted compound), a preparation method of the compound, pharmaceutical composition containing the compound and an application of the above components in pharmaceuticals.
Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors
Fidanze, Steven D.,Liu, Dachun,Mantei, Robert A.,Hasvold, Lisa A.,Pratt, John K.,Sheppard, George S.,Wang, Le,Holms, James H.,Dai, Yujia,Aguirre, Ana,Bogdan, Andrew,Dietrich, Justin D.,Marjanovic, Jasmina,Park, Chang H.,Hutchins, Charles W.,Lin, Xiaoyu,Bui, Mai H.,Huang, Xiaoli,Wilcox, Denise,Li, Leiming,Wang, Rongqi,Kovar, Peter,Magoc, Terrance J.,Rajaraman, Ganesh,Albert, Daniel H.,Shen, Yu,Kati, Warren M.,McDaniel, Keith F.
supporting information, p. 1804 - 1810 (2018/04/23)
Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin
Design and Activity of Specific Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitors for the Treatment of Clear Cell Renal Cell Carcinoma: Discovery of Clinical Candidate (S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1 H-inden-4-yl)oxy)-5-fluorobenzonitrile (PT2385)
Wehn, Paul M.,Rizzi, James P.,Dixon, Darryl D.,Grina, Jonas A.,Schlachter, Stephen T.,Wang, Bin,Xu, Rui,Yang, Hanbiao,Du, Xinlin,Han, Guangzhou,Wang, Keshi,Cao, Zhaodan,Cheng, Tzuling,Czerwinski, Robert M.,Goggin, Barry S.,Huang, Heli,Halfmann, Megan M.,Maddie, Melissa A.,Morton, Emily L.,Olive, Sarah R.,Tan, Huiling,Xie, Shanhai,Wong, Tai,Josey, John A.,Wallace, Eli M.
, p. 9691 - 9721 (2018/10/31)
HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel-Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n → π?Ar interaction to guide early analog design, the conformational restriction of an essential hydroxyl moiety, and the remarkable impact of fluorination near the hydroxyl group. Evaluation of select compounds from two structural classes in a sequence of PK/PD, efficacy, PK, and metabolite profiling identified 10i (PT2385, luciferase EC50 = 27 nM) as the clinical candidate. Finally, a retrospective crystallographic analysis describes the structural perturbations necessary for efficient antagonism.
Development of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as a novel chemical series of BRD4 inhibitors
Liu, Xueting,Wu, Zhenwei,Tian, Jiping,Yuan, Xinrui,Zhao, Leilei,Chen, Pan,Zhang, Huibin,Zhou, Jinpei
, p. 2089 - 2099 (2018/07/30)
Bromodomain protein 4 (BRD4) is a member of the bromodomain and extra-terminal domain (BET) protein family. It binds to acetylated histones that regulate gene transcription preferentially at super-enhancer regions. Now BRD4 has been involved into several
Methylpyrrole inhibitors of BET bromodomains
Hasvold, Lisa A.,Sheppard, George S.,Wang, Le,Fidanze, Steven D.,Liu, Dachun,Pratt, John K.,Mantei, Robert A.,Wada, Carol K.,Hubbard, Robbert,Shen, Yu,Lin, Xiaoyu,Huang, Xiaoli,Warder, Scott E.,Wilcox, Denise,Li, Leiming,Buchanan, F. Greg,Smithee, Lauren,Albert, Daniel H.,Magoc, Terrance J.,Park, Chang H.,Petros, Andrew M.,Panchal, Sanjay C.,Sun, Chaohong,Kovar, Peter,Soni, Nirupama B.,Elmore, Steven W.,Kati, Warren M.,McDaniel, Keith F.
supporting information, p. 2225 - 2233 (2017/04/27)
An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further mo
Design, synthesis and biological evaluation of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as BRD4 inhibitors
Zhao, Leilei,Yang, Yifei,Guo, Yahui,Yang, Lingyun,Zhang, Jian,Zhou, Jinpei,Zhang, Huibin
, p. 2482 - 2490 (2017/04/03)
BRD4 is an attractive target for antitumor due to its important role in regulation of gene transcription. In this paper, we synthesized a series of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as potent BRD4 inhibitors and evaluated their BRD4 inhibitory activities in vitro and anti-proliferation effects on tumor cells. Gratifyingly, compound 10j exhibited robust potency of BRD4(1) and BRD4(2) inhibition with IC50 values of 130 and 76?nM respectively. Docking studies were performed to explain the structure-activity relationship. Furthermore, compound 10j potently inhibited cell proliferation in BRD4-sensitive cell lines HL-60 and MV4-11 with IC50 value of 0.57 and 0.18?μM respectively. Activity on BRD4-independent K562 cell was weaker than on BRD4-sensitive lines. Overall, these results suggest that compound 10j is a potential BRD4 inhibitor deserving further investigation for cancer treatment.
Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor
McDaniel, Keith F.,Wang, Le,Soltwedel, Todd,Fidanze, Steven D.,Hasvold, Lisa A.,Liu, Dachun,Mantei, Robert A.,Pratt, John K.,Sheppard, George S.,Bui, Mai H.,Faivre, Emily J.,Huang, Xiaoli,Li, Leiming,Lin, Xiaoyu,Wang, Rongqi,Warder, Scott E.,Wilcox, Denise,Albert, Daniel H.,Magoc, Terrance J.,Rajaraman, Ganesh,Park, Chang H.,Hutchins, Charles W.,Shen, Jianwei J.,Edalji, Rohinton P.,Sun, Chaohong C.,Martin, Ruth,Gao, Wenqing,Wong, Shekman,Fang, Guowei,Elmore, Steven W.,Shen, Yu,Kati, Warren M.
supporting information, p. 8369 - 8384 (2017/11/03)
The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibi
BROMODOMAIN INHIBITORS
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, (2015/01/16)
The present invention provides for compounds of formula (I). wherein Rx, Ry, Rx1, L1, G1, A1, A2, A3, and A4 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).
DIHYDRO-PYRROLOPYRIDINONE INHIBITORS
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Paragraph 0892, (2014/09/29)
The present invention provides for compounds of formula (I) wherein R1, R2, R3, R4, and R5 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprising one or more compounds of formula (I).
