Discovery of L-791,943: a potent,selective, non emetic and orally active phosphodiesterase-4 inhibitor |
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Authors: | Guay Daniel Hamel Pierre Blouin Marc Brideau Christine Chan Chi Chung Chauret Nathalie Ducharme Yves Huang Zheng Girard Mario Jones Tom R Laliberté France Masson Paul McAuliffe Malia Piechuta Hanna Silva José Young Robert N Girard Yves |
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Institution: | Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada H9R 4P8. daniel_guay@merck.com |
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Abstract: | Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-alpha = 0.67 microM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey. |
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