207279-14-9Relevant academic research and scientific papers
Solubility-driven optimization of phosphodiesterase-4 inhibitors leading to a clinical candidate
Press, Neil J.,Taylor, Roger J.,Fullerton, Joseph D.,Tranter, Pamela,McCarthy, Clive,Keller, Thomas H.,Arnold, Nicola,Beer, David,Brown, Lyndon,Cheung, Robert,Christie, Julie,Denholm, Alastair,Haberthuer, Sandra,Hatto, Julia D. I.,Keenan, Mark,Mercer, Mark K.,Oakman, Helen,Sahri, Helene,Tuffnell, Andrew R.,Tweed, Morris,Tyler, John W.,Wagner, Trixie,Fozard, John R.,Trifilieff, Alexandre
, p. 7472 - 7479 (2012/11/06)
The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhib
[1,7]NAPHTHYRIDINES AS PDE4 INHIBITORS
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Page 16, (2008/06/13)
Compounds of Formula (I) in free or salt form, wherein R1, R2 and R3 have the meanings as indicated in the specification, are useful for treating conditions mediated by of phosphodiesterase type 4 or the down-regulation or inhibition of TNF-α release, particularly obstructive or inflammatory airways diseases. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
Palladium-catalyzed cross-coupling reactions for the synthesis of 6,8- disubstituted 1,7-naphthyridines: A novel class of potent and selective phosphodiesterase type 4D inhibitors
Hersperger, Rene,Bray-French, Katharine,Mazzoni, Lazzaro,Müller, Thomas
, p. 675 - 682 (2007/10/03)
Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC50 values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC50 value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D- selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
