- SUBSTITUTED 2- AMIDOQUINAZOL-4-ONES AS MATRIX METALLOPROTEINASE-13 INHIBITORS
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The present invention provides a novel amide derivative having a matrix metalloproteinase inhibitory activity, and useful as a pharmaceutical agent, which is a compound represented by the formula (I) wherein ring A is an optionally substituted, nitrogen containing heterocycle, ring B is an optionally substituted monocyclic homocycle or an optionally substituted monocyclic heterocycle, Z is N or NR1 (R1 is a hydrogen atom or an optionally substituted hydrocarbon group), is a single bond or a double bond, R2 is a hydrogen atom or an optionally substituted hydrocarbon group, X is an optionally substituted spacer having 1 to 6 atoms, ring C is (1) an optionally substituted homocycle or (2) an optionally substituted heterocycle other than a ring represented by (II) (X′ is S, O, SO, or CH2), and at least one of ring B and ring C has substituent(s), provided that N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]2 hydroxypropyl}5,6 dimethyl 4 oxo 1,4 dihydrothieno[2,3-d]pyrimidine-2-carboxamide is excluded, or a salt thereof.
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Paragraph 1548
(2015/12/23)
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- Pd(OAc)2-catalyzed alkoxylation of arylnitriles via sp 2 C-H bond activation using cyano as the directing group
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A Pd(OAc)2-catalyzed ortho-alkoxylation of arylnitrile was described. Using cyano as a directing group, the aromatic C-H bond can be functionalized efficiently to generate ortho-alkoxylated arylnitrile derivatives with moderate yields. The opti
- Li, Wu,Sun, Peipei
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p. 8362 - 8366
(2013/01/15)
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- Discovery of novel small molecule cell type-specific enhancers of NF-κB nuclear translocation
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An IKKβ inhibitor reported to block NF-κB transcriptional activities in Jurkat T cells, was found to enhance NF-κB translocation in HUVEC cells. These studies suggested a noncanonical NF-κB signaling pathway independent of IKKβ in HUVEC cells.
- Gong, Gangli,Xie, Yuli,Liu, Yidong,Rinderspacher, Alison,Deng, Shi-Xian,Feng, Yan,Zhu, Zhengxiang,Tang, Yufei,Wyler, Michael,Aulner, Nathalie,Toebben, Udo,Smith, Deborah H.,Branden, Lars,Chung, Caty,Schuerer, Stephan,Vidovic, Dusica,Landry, Donald W.
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scheme or table
p. 1191 - 1194
(2009/08/07)
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- Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy
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Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord that is caused by deletion and/or mutation of the survival motor neuron gene (SMN1). Adjacent to SMN1 are a variable number of copies of the SMN2 gene. The two genes essentially differ by a single nucleotide, which causes the majority of the RNA transcripts from SMN2 to lack exon 7. Although both SMN1 and SMN2 encode the same Smn protein amino acid sequence, the loss of SMN1 and incorrect splicing of SMN2 have the consequence that Smn protein levels are insufficient for the survival of motor neurons. The therapeutic goal of our medicinal chemistry effort was to identify small-molecule activators of the SMN2 promoter that, by up-regulating gene transcription, would produce greater quantities of full-length Smn protein. Our initial medicinal chemistry effort explored a series of C5 substituted benzyl ether based 2,4-diaminoquinazoline derivatives that were found to be potent activators of the SMN2 promoter; however, inhibition of DHFR was shown to be an off-target activity that was linked to ATP depletion. We used a structure-guided approach to overcome DHFR inhibition while retaining SMN2 promoter activation. A lead compound 11a was identified as having high potency (EC50 = 4 nM) and 2.3-fold induction of the SMN2 promoter. Compound 11a possessed desirable pharmaceutical properties, including excellent brain exposure and long brain half-life following oral dosing to mice. The piperidine compound 11a up-regulated expression of the mouse SMN gene in NSC-34 cells, a mouse motor neuron hybrid cell line. In type 1 SMA patient fibroblasts, compound 11a induced Smn in a dose-dependent manner when analyzed by immunoblotting and increased the number of intranuclear particles called gems. The compound restored gems numbers in type I SMA patient fibroblasts to levels near unaffected genetic carriers of SMA.
- Thurmond, John,Butchbach, Matthew E. R.,Palomo, Marty,Pease, Brian,Rao, Munagala,Bedell, Louis,Keyvan, Monica,Pai, Grace,Mishra, Rama,Haraldsson, Magnus,Andresson, Thorkell,Bragason, Gisli,Thosteinsdottir, Margret,Bjornsson, Jon Mar,Coovert, Daniel D.,Burghes, Arthur H. M.,Gurney, Mark E.,Singh, Jasbir
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p. 449 - 469
(2008/09/18)
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- The Reactions of 2,4-Dinitro- and 2,6-Dinitro-benzonitriles with Methoxide Ions
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The reactions of 1-cyano-2,4-dinitrobenzene (1) and 1-cyano-2,6-dinitrobenzene (2) with methoxide ions in methanol or in 98/2 (v/v) DMSO/methanol have been examined by uv/visible and 1H n.m.r. spectroscopies.In methanol reaction occurs in two stages.In the first there is competitive attack by methoxide at the cyano-group, leading to the solvate, and at ring-carbon atoms leading to substitution products.In the second stage the solvate is converted to substitution products via the parent.Rate coefficients are reported for methoxide attack and equilibrium constants for solvate formation have been calculated.The initial reversible reactions in DMSO give ?-adducts by methoxide attack at unsubstituted ring-positions and these are followed by irreversible substitution of nitro-groups.
- Crampton, Michael R.,Elsegood, Simon E.,Atherton, John H.
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p. 1371 - 1382
(2007/10/02)
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- Antifolate and Antibacterial Activities of 5-Substituted 2,4-Diaminoquinazolines
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A series of 5-substituted 2,4-diaminoquinazolines (3) has been synthesized and evaluated as inhibitors of the enzyme dihydrofolate reductase (DHFR) from both bacterial and mammalian sources.The best compounds (e.g. 53) show good activity against Escherichia coli DHFR, but there is no significant selectivity for the bacterial over the mammalian enzyme.The structure-activity relationships for enzyme inhibition appear to be complex and not amenable to simple analysis; a hypotesis to explain the observed qualitative structure-activity relationships is proposed.The inhibitory activities of the compounds against the growth of intact bacterial cells in vitro closely parallel those for the inhibition of the isolated bacterial enzymes, suggesting that their antifolate action is responsible for their antibacterial effects.Five of the compounds were tested for their ability to cure a systemic E. coli infection in the mouse, but they showed no therapeutic effects at their maximum tolerated doses.
- Harris, Neil V.,Smith, Christopher,Bowden, Keith
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p. 434 - 444
(2007/10/02)
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- Oxanilic acids, a new series of orally active antiallergic agents
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A large number of oxanilic acid esters and N heteroaryl oxamic acid esters were prepared and found to have antiallergic activity using the rat passive cutaneous anaphylaxis (PCA) test. Many of the oxanilic acid esters are active orally, with the most active species having an aryl 2' carbamoyl group and a 3' methoxy group. Hydrolysis of the ester from the oxanilic ester moiety causes a loss of oral activity.
- Sellstedt,Guinosso,Begany,Bell,Rosenthale
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p. 926 - 933
(2007/10/05)
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