- 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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supporting information
p. 4084 - 4089
(2014/09/29)
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- FLUOROQUINOLONE DERIVATIVES FOR OPHTHALMIC APPLICATIONS
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The present invention relates to fluoroquinolone derivatives having enhanced ocular penetration characteristics and/or antimicrobial activity, and to compositions comprising such derivatives. The derivatives and compositions are particularly well suited for treating ophthalmic bacterial infections. The present invention more particularly relates to the discovery that a 2-methyl substitution on a diazabicyclo group attached to a fluoroquinolone ring system produces improved permeability characteristics, and that a 5-amino substitution on a fluoroquinolone ring system results in improved anti-microbial activity.
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- Process for preparing acids via alpha-chloroepoxy esters
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This invention relates to a method for preparing certain acids of formula (I) via a chloroepoxy ester, which are useful as phosphodiesterase 4 inhibitors.
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- A practical synthesis of the PDE4 inhibitor, SB-207499, from a cyclohexanone precursor
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The synthesis of SB-207499 is described. Investigation and development of new strategies for the homologation of ketone, 4-cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-cyclohexan-1-one 2 are described which produce SB-207499. Our ultimate route of synthesis to SB-207499 is robust and operationally simple and produces the final drug substance in good yield and purity.
- Badham, Neil F.,Chen, Jian-Hao,Cummings, Paul G.,Dell'Orco, Philip C.,Diederich, Ann M.,Eldridge, Ann M.,Mendelson, Wilford L.,Mills, Robert J.,Novack, Vance J.,Olsen, Mark A.,Rustum, Abu M.,Webb, Kevin S.,Yang, Shawn
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p. 101 - 108
(2013/09/05)
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- Process and intermediates for making 4-cyanosubstituted cyclohexanoic acids
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Herein is provided a process for preparing substituted cyclohexanoic acids of formula (I), where Rais a carbon-containing group optionally linked by oxygen, sulfur or nitrogen to the phenyl ring and j is 1-5; and one of R and R* is hydrogen and the other is C(O)OH.
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- Compounds and method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids
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This invention relates to a method of preparing a compound of the following type by treating a compound of formula (II) with lithium bromide, magnesium bromide and the like.
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- Method for treating COPD
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A method for treating COPD is disclosed comprising administering compounds of Formula (I) wherein the terms R1, R3, X, X2and Z are herein defined.
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- Rearrangement of epoxynitriles: A convenient homologation of acyclic and cyclic ketones to carboxylic acids
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A convenient two-step homologation of both aliphatic and aromatic ketones to the corresponding carboxylic acid has been developed. First ketones were converted to epoxynitriles with the Darzens reaction. Second, a Lewis acid mediated rearrangement of these epoxynitriles with lithium bromide was achieved to give homologated secondary alkanoic acids (as well as aryl-alkanoic) in good yields. The mechanism and the scope of the rearrangement reaction were investigated. This strategy constitutes a two- step homologation of ketones to secondary carboxylic acids.
- Badham, Neil F.,Mendelson, Wilford L.,Allen, Andrew,Diederich, Ann M.,Eggleston, Drake S.,Filan, John J.,Freyer, Alan J.,Killmer Jr., Lewis B.,Kowalski, Conrad J.,Liu, Li,Novack, Vance J.,Vogt, Frederick G.,Webb, Kevin S.,Yang, Jennifer
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p. 5440 - 5443
(2007/10/03)
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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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- Compounds useful for treating allergic and inflammatory diseases
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Novel compounds or formula (I) are described herein. These compounds inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production. The compounds or the present invention are also useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase IV and are therefore useful in the treatment of disease states in need of mediation or inhibition therefore. STR1
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- Compounds useful for treating allergic and inflammatory diseases
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Novel compounds of Formula (I) STR1 where X4 is a substituted cyclohexane or cyclohexane group and the other radicals are defined herein. These compounds inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production. The compounds of the present invention are also useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase IV and are therefore useful in the treatment of disease states in need of mediation or inhibition thereof.
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