The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors |
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| Authors: | Renee Aspiotis Denis Deschênes Daniel Dubé Yves Girard Zheng Huang France Laliberté Susana Liu Robert Papp Donald W Nicholson Robert N Young |
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| Institution: | Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Hwy, Kirkland, Québec., Canada H9H 3L1 |
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| Abstract: | The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50 = 0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized. |
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