Solubility-Driven Optimization of Phosphodiesterase-4 Inhibitors Leading to a Clinical Candidate

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• 作者：Neil J. Press ; Roger J. Taylor ; Joseph D. Fullerton ; Pamela Tranter ; Clive McCarthy ; Thomas H. Keller ; Nicola Arnold ; David Beer ; Lyndon Brown ; Robert Cheung ; Julie Christie ; Alastair Denholm ; Sandra Haberthuer ; Julia D. I. Hatto ; Mark Keenan ; Mark K. Mercer ; Helen Oakman ; Helene Sahri ; Andrew R. Tuffnell ; Morris Tweed ; John W. Tyler ; Trixie Wagner ; John R. Fozard ; Alexandre Trifilieff
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7472-7479
• 全文大小：357K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

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.