- Repurposing human PDE4 inhibitors for neglected tropical diseases: Design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors
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A medicinal chemistry exploration of the human phosphodiesterase 4 (hPDE4) inhibitor cilomilast (1) was undertaken in order to identify inhibitors of phosphodiesterase B1 of Trypanosoma brucei (TbrPDEB1). T. brucei is the parasite which causes African sleeping sickness, a neglected tropical disease that affects thousands each year, and TbrPDEB1 has been shown to be an essential target of therapeutic relevance. Noting that 1 is a weak inhibitor of TbrPDEB1, we report the design and synthesis of analogs of this compound, culminating in 12b, a sub-micromolar inhibitor of TbrPDEB1 that shows modest inhibition of T. brucei proliferation.
- Amata, Emanuele,Bland, Nicholas D.,Hoyt, Charles T.,Settimo, Luca,Campbell, Robert K.,Pollastri, Michael P.
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- Design, synthesis and biological evaluation of substituted aminopyridazin-3(2H)-ones as G0/G1-phase arresting agents with apoptosis-inducing activities
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A series of aminopyridazin-3(2H)-one derivatives has been designed and synthesized. Their antiproliferative activities were evaluated against three human cancer cell lines (SH-SY5Y human neuroblastoma, K562 human myelogenous leukemia and AGS gastric cancer cell lines) using the MTT assay. The preliminary activity test displayed that compound 8a exhibited comparable activities against all test cells with the positive control fluorouracil. Meanwhile compounds 8b, 8e and 9c-e displayed selective antiproliferative activities for SH-SY5Y cells. Furthermore, compounds 8a-b with low-micromole GI50 value for SH-SY5Y cells induced apoptosis with cell cycle arrest at G0/G1 phase in SH-SY5Y cells in a dose-dependent manner.
- Ge, Bing-Chen,Feng, Hong-Fang,Cheng, Yu-Fang,Wang, Hai-Tao,Xi, Bao-Ming,Yang, Xue-Mei,Xu, Jiang-Ping,Zhou, Zhong-Zhen
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supporting information
p. 440 - 445
(2017/10/17)
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- Catechol diethers as selective PDE IV inhibitors
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This invention relates to 4-substituted catechol diether compounds which are selective inhibitors of phosphodiesterase (PDE) type IV. The compounds of the present invention are useful in inhibiting PDE IV and in the treatment of AIDS, asthma, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases. This invention also relates to pharmaceutical compositions comprising the compounds hereof
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- 1,4-Cyclohexanecarboxylates: Potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma
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Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid (1, SB 207499, Ariflo(TM)), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.
- Christensen, Siegfried B.,Guider, Aimee,Forster, Cornelia J.,Gleason, John G.,Bender, Paul E.,Karpinski, Joseph M.,Dewolf Jr., Walter E.,Barnette, Mary S.,Underwood, David C.,Griswold, Don E.,Cieslinski, Lenora B.,Burman, Miriam,Bochnowicz, Steven,Osborn, Ruth R.,Manning, Carol D.,Grous, Marilyn,Hillegas, Leonard M.,Bartus, Joan O'Leary,Dominic Ryan,Eggleston, Drake S.,Curtis Haltiwanger,Torphy, Theodore J.
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p. 821 - 835
(2007/10/03)
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- PHENYLALKYL OXAMIDES
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Novel oxamide derivatives are described which inhibit the production of TNF and are useful in the treatment of disease states mediated or exacerbated by TNF production. The compounds of the present invention are also useful as inhibitors of PDE IV and are therefor useful in the treatment of disease states mediated or exacerbated thereby
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