- Discovery of 3,5-dimethylisoxazole derivatives as novel, potent inhibitors for bromodomain and extraterminal domain (BET) family
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Bromodomain and extra-terminal (BET) is a promising therapeutic target for various hematologic cancers. We used the BRD4 inhibitor compound 13 as a lead compound to develop a variety of compounds, and we introduced diverse groups into the position of the compound 13 orienting toward the ZA channel. A series of compounds (14–23, 38–41, 43, 47–49) bearing triazolopyridazine motif exhibited remarkable BRD4 protein inhibitory activities. Among them, compound 39 inhibited BRD4(BD1) protein with an IC50 of 0.003 μM was superior to lead compound 13. Meanwhile, compound 39 possess activity, IC50 = 2.1 μM, in antiproliferation activity against U266 cancer cells. On the other hand, compound 39 could arrest tumor cells into the G0/G1 phase and induce apoptosis, which was consistent with its results in inhibiting cell proliferation. Biological and biochemical data suggest that BRD4 protein might be a therapeutic target and that compound 39 is an excellent lead compound for further development.
- Fang, Lincheng,Hu, Zhaoxue,Yang, Yifei,Chen, Pan,Zhou, Jinpei,Zhang, Huibin
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- Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents
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The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPARδ agonists would increase insulin secretion and sensibility by FFA1 and PPARδ activation. In this study, we hybrid FFA1 agonist AM-4668 with PPARδ agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPARs. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPARδ agonist could be a valuable therapy for type 2 diabetes.
- Li, Zheng,Chen, Yueming,Zhou, Zongtao,Deng, Liming,Xu, Yawen,Hu, Lijun,Liu, Bing,Zhang, Luyong
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p. 352 - 365
(2019/01/04)
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- Biphenyl heterocyclic derivatives, their preparation and their use as medicaments (by machine translation)
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The present invention relates to a novel biphenyl heterocyclic derivative represented by a general formula (I) and a preparation method thereof and use of a pharmaceutical composition containing the derivative for preparation of a drug for treating diabetes. The biphenyl heterocyclic derivative has extremely excellent hypoglycemic activity in vivo, and excellent in vivo safety and low liver toxicity risk of the compound having such a structure are unexpectedly found, and the novel biphenyl heterocyclic derivative may be used for preventing or treating diabetes.
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Paragraph 0303-0306; 0328-0331
(2018/06/21)
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- URIDINE NUCLEOSIDE DERIVATIVES, COMPOSITIONS AND METHODS OF USE
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This disclosure relates to uridine nucleoside derivatives, compositions comprising therapeutically effective amounts of those nucleoside derivatives and methods of using those nucleoside derivatives or compositions in treating disorders that are responsive to compounds, such as agonists, of P2Y6 receptor, e.g., neuronal disorders, including neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease) and traumatic CNS injury, pain, Down Syndrome (DS), glaucoma and inflammatory conditions.
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Paragraph 0192; 0199; 0261
(2018/04/20)
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- Design, synthesis, and biological evaluation of N,N-disubstituted-4-arylthiazole-2-methylamine derivatives as cholesteryl ester transfer inhibitors
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Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide linker by heterocyclic aromatics and then a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were designed by utilizing a conformational restriction strategy. Thirty-six compounds were synthesized and evaluated for their CETP inhibitory activities. Structure-activity relationship studies indicate that electron donor groups substituted ring A, and electron-withdrawing groups at the 4-position of ring B were critical for potency. Among these compounds, compound 30 exhibited excellent CETP inhibitory activity (IC50 = 0.79 ± 0.02 μM) in vitro and showed an acceptable metabolic stability.
- Wang, Xinran,Lin, Xuehua,Xu, Xuanqi,Li, Wei,Hao, Lijuan,Liu, Chunchi,Zhao, Dongmei,Cheng, Maosheng
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- Design, synthesis and Structure-activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes
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The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.
- Li, Zheng,Qiu, Qianqian,Xu, Xue,Wang, Xuekun,Jiao, Lei,Su, Xin,Pan, Miaobo,Huang, Wenlong,Qian, Hai
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supporting information
p. 246 - 257
(2016/03/08)
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- 1-AZA-BICYCLO [2.2.2] OCTANE DERIVATIVES USEFUL AS MUSCARINIC RECEPTOR ANTAGONISTS
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The invention provides named compounds of formula (I), pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions and their use in therapy.
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Page/Page column 56
(2010/01/12)
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- Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2: Synthesis, x-ray crystallographic analysis, and biological activities
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High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC50 values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase α (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.
- Kim, Kyoung Soon,Kimball, S. David,Misra, Raj N.,Rawlins, David B.,Hunt, John T.,Xiao, Hai-Yun,Lu, Songfeng,Qian, Ligang,Han, Wen-Ching,Shan, Weifang,Mitt, Toomas,Cai, Zhen-Wei,Poss, Michael A.,Zhu, Hong,Sack, John S.,Tokarski, John S.,Chang, Chieh Ying,Pavletich, Nikola,Kamath, Amrita,Humphreys, William G.,Marathe, Punit,Bursuker, Isia,Kellar, Kristen A.,Roongta, Urvashi,Batorsky, Roberta,Mulheron, Janet G.,Bol, David,Fairchild, Craig R.,Lee, Francis Y.,Webster, Kevin R.
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p. 3905 - 3927
(2007/10/03)
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- Synthesis and Evaluation of 2-Pyridinone Derivatives as HIV-1-Specific Reverse Transcriptase Inhibitors. 2. Analogues of 3-Aminopyridin-2(1H)-one
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A series of nonnulceoside 3-aminopyridin-2(1H)-one derivatives was synthesized and evaluated for HIV-1 RT inhibitory properties.Several analogs proved to be potent and highly selective antagonists with in vitro IC50 values as low as 19 nM in the enzyme assay using rC*dG as template*primer.Two compounds from this series, 3-amino>-5-ethyl-6-methylpyridin-2(1H)-one (34, L-697,639) and the corresponding 4,7-dichloro analogue (37, L-697,661) inhibited the spread of HIV-1 IIIb infection by 95percent in MT4 cell culture at concentrations of 25-50 nM and were selected for clinical trials as antiviral agents.
- Saari, Walfred S.,Wai, John S.,Fisher, Thorsten E.,Thomas, Craig M.,Hoffman, Jacob M.,et al.
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p. 3792 - 3802
(2007/10/02)
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- Formation and Reaction of Oxazoles. Synthesis of N-Substituted 2-(Aminomethyl)oxazoles
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The BF3-catalyzed reaction of substituted α-diazoacetophenones with chloroacetonitrile gave 5-aryl-2-chloromethyloxazoles (3) in high yields.Methyl p-nitrophenyldiazoacetate also yielded 2-(chloromethyl)-5-methoxy-4-(p-nitrophenyl)oxazole.The nucleophilic substitution of 3 with primary, secondary, and tertiary amines afforded the corresponding secondary amines, tertiary amines, and quaternary anmmonium salts bearing a 2-oxazolylmethyl group.
- Ibata, Toshikazu,Isogami, Yasushi
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p. 618 - 620
(2007/10/02)
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- Reactions of β-Azidostyrenes with Halogenoacetic Acid. A novel Formation of Oxazoles
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The reaction of β.azidostyrene with trifluoro-, trichloro-, or monochloro-acetic acid gave 2-halogenomethyl-5-phenyloxazole via attack of halogenoacetate anion on a benzylic carbocation or a conjugate acid of the azide.
- Takeuchi, Hiroshi,Kitamura, Yasunori,Hayakawa, Satoshi,Koyama, Kikuhiko
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p. 1414 - 1415
(2007/10/02)
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- Phenylpiperazine derivatives
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Phenylpiperazine derivatives of formula (I): STR1 where R1 is benzyl, C1-6 alkyl or optionally substituted phenyl; R2 is optionally substituted phenyl; R3 is hydrogen or C1-4 alkyl; Q is furan, thioph
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