2. Academic Validation
  3. Discovery of L-791,943: a potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor

Discovery of L-791,943: a potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor

  • Bioorg Med Chem Lett. 2002 Jun 3;12(11):1457-61. doi: 10.1016/s0960-894x(02)00190-7.
Daniel Guay 1,  Pierre Hamel,  Marc Blouin,  Christine Brideau,  Chi Chung Chan,  Nathalie Chauret,  Yves Ducharme,  Zheng Huang,  Mario Girard,  Tom R Jones,  France Laliberté,  Paul Masson,  Malia McAuliffe,  Hanna Piechuta,  José Silva,  Robert N Young,  Yves Girard
Affiliations

Affiliation

  • 1 Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada H9R 4P8. daniel_guay@merck.com
PMID: 12031319 DOI: 10.1016/s0960-894x(02)00190-7
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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