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J Med Chem. 2012 Sep 13;55(17):7472-9. doi: 10.1021/jm300459a. Epub 2012 Aug 30.

Solubility-driven optimization of phosphodiesterase-4 inhibitors leading to a clinical candidate.

Author information

1
Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K. neil.press@novartis.com

Abstract

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 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.

PMID:
22889281
DOI:
10.1021/jm300459a
[Indexed for MEDLINE]

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