40034-44-4Relevant articles and documents
Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1 H)-ones as Polypharmacological Inhibitors of BET and Kinases
Lv, Kaikai,Chen, Weicong,Chen, Danqi,Mou, Jie,Zhang, Huijie,Fan, Tiantian,Li, Yanlian,Cao, Danyan,Wang, Xin,Chen, Lin,Shen, Jingkang,Pei, Dongsheng,Xiong, Bing
, p. 9787 - 9802 (2020)
Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with a typical kinase hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-one, we demonstrated that this rational design can produce high potent inhibitors of CDK9 and BET proteins. In this series, compound 40 was identified as the potential lead compound with balanced activities of BRD4 (IC50 = 12.7 nM) and CDK9 (IC50 = 22.4 nM), as well as good antiproliferative activities on a small cancer cell panel. Together, the current study provided a new method for the discovery of bromodomain and kinase dual inhibitors rather than only being discovered by serendipity.
DIARYLUREAS AS CB1 ALLOSTERIC MODULATORS
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Paragraph 69; 126; 131, (2018/12/02)
The present invention provides novel diarylurea derivatives (compounds of formula (I)) and their uses. The compounds of the present invention are demonstrated to be allosteric modulators of the CB1 receptor, and therefore useful for the treatment of diseases and conditions mediated by CB1.
Copper mediated C-H amination with oximes: En route to primary anilines
Xu, Lin-Lin,Wang, Xing,Ma, Biao,Yin, Ming-Xing,Lin, Hai-Xia,Dai, Hui-Xiong,Yu, Jin-Quan
, p. 5160 - 5164 (2018/06/21)
Here we report an efficient Cu(i)-mediated C-H amination reaction with oximes as amino donors to introduce NH2 groups directly. Various strongly coordinating heterocycles including quinoline, pyrimidine, pyrazine, pyrazole and triazole were tolerated well. The potential utility was further demonstrated in a late-stage modification of telmisartan (an antagonist for the angiotensin II receptor).
Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution
Nguyen, Thuy,German, Nadezhda,Decker, Ann M.,Langston, Tiffany L.,Gamage, Thomas F.,Farquhar, Charlotte E.,Li, Jun-Xu,Wiley, Jenny L.,Thomas, Brian F.,Zhang, Yanan
, p. 7410 - 7424 (2017/09/22)
Allosteric modulators of the cannabinoid CB1 receptor have recently been reported as an alternative approach to modulate the CB1 receptor for therapeutic benefits. In this study, we report the design and synthesis of a series of diarylureas derived from PSNCBAM-1 (2). Similar to 2, these diarylureas dose-dependently inhibited CP55,940-induced intracellular calcium mobilization and [35S]GTP-γ-S binding while enhancing [3H]CP55,940 binding to the CB1 receptor. Structure-activity relationship studies revealed that the pyridinyl ring of 2 could be replaced by other aromatic rings and the pyrrolidinyl ring is not required for CB1 allosteric modulation. 34 (RTICBM-74) had similar potencies as 2 in all in vitro assays but showed significantly improved metabolic stability to rat liver microsomes. More importantly, 34 was more effective than 2 in attenuating the reinstatement of extinguished cocaine-seeking behavior in rats, demonstrating the potential of this diarylurea series as promising candidates for the development of relapse treatment of cocaine addiction.
Discovery and optimization of a novel series of GPR142 agonists for the treatment of type 2 diabetes mellitus
Lizarzaburu, Mike,Turcotte, Simon,Du, Xiaohui,Duquette, Jason,Fu, Angela,Houze, Jonathan,Li, Leping,Liu, Jinqian,Reagan, Jeff,Yu, Ming,Medina, Julio C.,Murakoshi, Michiko,Oda, Kozo,Okuyama, Ryo,Nara, Futoshi
, p. 5942 - 5947,6 (2020/07/30)
The discovery and initial optimization of a series of phenylalanine based agonists for GPR142 is described. The structure-activity-relationship around the major areas of the molecule was explored to give agonists 90 times more potent than the initial HTS hit in a human GPR142 inositol phosphate accumulation assay. Removal of CYP inhibition by exploration of the pyridine A-ring is also described.
SAR studies of 4-pyridyl heterocyclic anilines that selectively induce autophagic cell death in von Hippel-Lindau-deficient renal cell carcinoma cells
Bonnet, Muriel,Flanagan, Jack U.,Chan, Denise A.,Lai, Edwin W.,Nguyen, Phuong,Giaccia, Amato J.,Hay, Michael P.
supporting information; experimental part, p. 3347 - 3356 (2011/07/09)
We recently identified a class of pyridyl aniline thiazoles (PAT) that displayed selective cytotoxicity for von Hippel-Lindau (VHL) deficient renal cell carcinoma (RCC) cells in vitro and in vivo. Structure-activity relationship (SAR) studies were used to develop a comparative molecular field analysis (CoMFA) model that related VHL-selective potency to the three-dimensional arrangement of chemical features of the chemotype. We now report the further molecular alignment-guided exploration of the chemotype to discover potent and selective PAT analogues. The contribution of the central thiazole ring was explored using a series of five- and six-membered ring heterocyclic replacements to vary the electronic and steric interactions in the central unit. We also explored a positive steric CoMFA contour adjacent to the pyridyl ring using Pd-catalysed cross-coupling Suzuki-Miyaura, Sonogashira and nucleophilic displacement reactions to prepare of a series of aryl-, alkynyl-, alkoxy- and alkylamino-substituted pyridines, respectively. In vitro potency and selectivity were determined using paired RCC cell lines: the VHL-null cell line RCC4 and the VHL-positive cell line RCC4-VHL. Active analogues selectively induced autophagy in RCC4 cells. We have used the new SAR data to further develop the CoMFA model, and compared this to a 2D-QSAR method. Our progress towards realising the therapeutic potential of this chemotype as a targeted cytotoxic therapy for the treatment of RCC by exploiting the absence of the VHL tumour suppressor gene is reported.
PHENYLALANINE AMIDE DERIVATIVES USEFUL FOR TREATING INSULIN-RELATED DISEASES AND CONDITIONS
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, (2010/09/03)
Provided herein are compounds of formula I: wherein A, B, X, R1 , R2 and subscript n are as defined in the following disclosure. Compositions comprising the compounds are also provided, as well as methods for their use, for example, in treatment of type 2 diabetes and type 2 diabetes-related conditions
Structurally simple inhibitors of lanosterol 14α-demethylase are efficacious in a rodent model of acute Chagas disease
Suryadevara, Praveen Kumar,Olepu, Srinivas,Lockman, Jeffrey W.,Ohkanda, Junko,Karimi, Mandana,Verlinde, Christophe L. M. J.,Kraus, James M.,Schoepe, Jan,Van Voorhis, Wesley C.,Hamilton, Andrew D.,Buckner, Frederick S.,Gelb, Michael H.
experimental part, p. 3703 - 3715 (2010/04/24)
We report structure-activity studies of a large number of dialkyl imidazoles as inhibitors of Trypanosoma cruzi lanosterol-14α-demethylase (L14DM). The compounds have a simple structure compared to posaconazole, another L14DM inhibitor that is an anti-Chagas drug candidate. Several compounds display potency for killing T. cruzi amastigotes in vitro with values of EC 50 in the 0.4-10 nM range. Two compounds were selected for efficacy studies in a mouse model of acute Chagas disease. At oral doses of 20-50 mg/kg given after establishment of parasite infection, the compounds reduced parasitemia in the blood to undetectable levels, and analysis of remaining parasites by PCR revealed a lack of parasites in the majority of animals. These dialkyl imidazoles are substantially less expensive to produce than posaconazole and are appropriate for further development toward an anti-Chagas disease clinical candidate.
Structure-activity relationships of 3,4-dihydro-1H-quinazolin-2-one derivatives as potential CDK5 inhibitors
Rzasa, Robert M.,Kaller, Matthew R.,Liu, Gang,Magal, Ella,Nguyen, Thomas T.,Osslund, Timothy D.,Powers, David,Santora, Vincent J.,Viswanadhan, Vellarkad N.,Wang, Hui-Ling,Xiong, Xiaoling,Zhong, Wenge,Norman, Mark H.
, p. 6574 - 6595 (2008/03/27)
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that plays a critical role in the early development of the nervous system. Deregulation of CDK5 is believed to contribute to the abnormal phosphorylation of various cellular substrates associated with neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Acyclic urea 3 was identified as a potent CDK5 inhibitor and co-crystallographic data of urea 3/CDK2 enzyme were used to design a novel series of 3,4-dihydroquinazolin-2(1H)-ones as CDK5 inhibitors. In this investigation we present our synthetic studies toward this series of compounds and discuss their biological relevance as CDK5 inhibitors.
Method for treating neoplasia with amino or pyridylamino cyclobutene derivatives
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, (2008/06/13)
A method for inhibiting neoplasia, particularly cancerous and precancerous lesions by exposing the affected cells to amino or pyridylamino cyclobutane derivatives.
