- Design, synthesis and biological evaluation of ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors
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We report herein the synthesis of novel ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors and the evaluation of pharmaceutical activity against five cancer cell lines (MDA-MB-231, BXPC-3, NCI-H1975, DU145 and 786O). Generally, the majority of compounds displayed strong anti-FAK enzymatic potencies (IC50 1 nM) and could effectively inhibit several class of cancer cell lines within the concentration of 3 μM in comparison with GSK2256098 as a reference. Among them, compound 4o is considered to be the most effective due to high sensitivity in antiproliferation. In culture, 4o could not only inhibit FAK Y397 phosphorylation in MDA-MB-231 cell line, but also trigger apoptosis in a dose-dependent manner. Furthermore, computational docking analysis also suggested that 4o and TAE-226 displayed the similar interaction with FAK kinase domain.
- Xie, Hongming,Lin, Xinglong,Zhang, Yingjun,Tan, Fuxing,Chi, Bo,Peng, Zhihong,Dong, Wanrong,An, Delie
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- MACROCYCLIC FUSED PYRRAZOLES AS MCL-1 INHIBITORS
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Provided are compounds represented by Formula IA: (IA), and the pharmaceutically acceptable salts and solvates thereof, wherein R, R 1a, R 1b, L 1, L 2, L 3, X, A, B and C are as defined as set forth
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- Focal adhesion kinase inhibitor and use
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The invention belongs to the field of medicines, relates to a focal adhesion kinase inhibitor and use, in particular relates to a novel focal adhesion kinase inhibitor compound, or stereoisomers, geometric isomers, tautomers, oxynitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, further relates to the use of the compound and pharmaceutical compositions as medicines, in particular the use of the compound and pharmaceutical compositions in manufacture of medicines for treatment or prevention of cancer, pulmonary hypertension, and pathological angiogenesis-related diseases.
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- A novel series of metabotropic glutamate receptor 5 negative allosteric modulators based on a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine core
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A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo testing. A lead molecule from the series demonstrated dose-dependent activity in the second phase of the rat formalin test from 30 mg/kg, and a preliminary PK/PD relationship was established.
- Duvey, Guillaume,Perry, Benjamin,Le Poul, Emmanuel,Poli, Sonia,Bonnet, Beatrice,Lambeng, Nathalie,Charvin, Delphine,Donovan-Rodrigues, Tansy,Haddouk, Hasnaà,Gagliardi, Stefania,Rocher, Jean-Philippe
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p. 4523 - 4527
(2013/08/23)
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- The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics
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This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.2,3.
- Rawson, David J.,Ballard, Stephen,Barber, Christopher,Barker, Laura,Beaumont, Kevin,Bunnage, Mark,Cole, Susan,Corless, Martin,Denton, Stephen,Ellis, David,Floc'H, Marion,Foster, Laura,Gosset, James,Holmwood, Frances,Lane, Charlotte,Leahy, David,Mathias, John,Maw, Graham,Million, William,Poinsard, Cedric,Price, Jenny,Russel, Rachel,Street, Stephen,Watson, Lesa
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experimental part
p. 498 - 509
(2012/03/08)
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- Identification of fused bicyclic heterocycles as potent and selective 5-HT2A receptor antagonists for the treatment of insomnia
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A series of fused bicyclic heterocycles was identified as potent and selective 5-HT2A receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.
- Xiong, Yifeng,Ullman, Brett,Choi, Jin-Sun Karoline,Cherrier, Martin,Strah-Pleynet, Sonja,Decaire, Marc,Feichtinger, Konrad,Frazer, John M.,Yoon, Woo H.,Whelan, Kevin,Sanabria, Erin K.,Grottick, Andrew J.,Al-Shamma, Hussien,Semple, Graeme
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p. 1870 - 1873
(2012/04/17)
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- Bicyclic Pyridinylpyrazoles
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Bicyclic pyridinylpyrazoles of the formula (I) in which the symbols have the meanings given in the description and agrochemically active salts thereof and their use for controlling unwanted microorganisms in crop protection and the protection of materials
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Page/Page column 28
(2011/10/19)
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- 2H-PYRAZOLO [4,3-D]PYRIMIDIN-5-AMINE DERIVATIVES AS H4 HISTAMINE RECEPTOR ANTAGONISTS FOR THE TREATMENT OF ALLERGIC, IMMUNOLOGICAL AND INFLAMMATORY DISEASES
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Pyrazolopyrimidine derivatives of formula (I), wherein the meaning of the different substituents are those indicated in the description. These compounds are useful as histamine H4 receptor antagonists.
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Page/Page column 101
(2010/04/30)
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- Structure-activity relationship of 6-methylidene penems bearing 6,5 bicyclic heterocycles as broad-spectrum β-lactamase inhibitors: Evidence for 1,4-thiazepine intermediates with C7 R stereochemistry by computational methods
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The design and synthesis of a series of 6-methylidene penems containing [6,5]-fused bicycles (thiophene, imidazole, or pyrazle-fused system) as novel class A, B, and C β-lactamase inhibitors is described. These penems proved to be potent inhibitors of the TEM-1 (class A) and AmpC (class C) β-lactamases and less so against the class B metallo-β-lactamase CcrA. Their in vitro and in vivo activities in combination with piperacillin are discussed. On the basis of the crystallographic structures of a serine-bound reaction intermediate of 2 with SHV-1 (class A) and GC1 (class C) enzymes, compounds 14a-1 were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C β-lactamases. The interaction energy calculation for the enzyme-bound intermediates favor the formation of the C7 R enantiomer over the S enantiomer of the 1,4-thiazepine in both β-lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.
- Venkatesan, Aranapakam M.,Agarwal, Atul,Abe, Takao,Ushirogochi, Hideki,Yamamura, Itsuka,Ado, Mihira,Tsuyoshi, Takasaki,Dos Santos, Osvaldo,Gu, Yansong,Sum, Fuk-Wah,Li, Zhong,Francisco, Gerry,Lin, Yang-I.,Petersen, Peter J.,Yang, Youjun,Kumagai, Toshio,Weiss, William J.,Shlaes, David M.,Knox, James R.,Mansour, Tarek S.
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p. 4623 - 4637
(2007/10/03)
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- BICYCLIC 6-ALKYLIDENE-PENEMS AS ?-LACTAMASES INHIBITORS
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The present invention provides a compound of Formula (I), pharmaceutical compositions and the use thereof for the treatment of bacterial infection or disease in a patient in need thereof.
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Page/Page column 69
(2008/06/13)
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- ALKYL N-NITRO- AND N-NITROSOPIPERIDIN-2-YLCARBAMATES
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N-nitro- and N-nitrosopipecolic acid 1 and 6 were converted to 1-nitro- and 1-nitroso-2-aminopiperidine.The amines were isolated as methyl carbamate derivatives 4 and 11.
- Kumar, Govindarajulu,Boyer, Joseph H.
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p. 481 - 484
(2007/10/02)
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