2. Academic Validation
  3. Optimization of a tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors: structure-activity relationship related to PDE4 inhibition and human ether-a-go-go related gene potassium channel binding affinity

Optimization of a tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors: structure-activity relationship related to PDE4 inhibition and human ether-a-go-go related gene potassium channel binding affinity

  • J Med Chem. 2003 Jun 5;46(12):2413-26. doi: 10.1021/jm0204542.
Richard W Friesen 1,  Yves Ducharme,  Richard G Ball,  Marc Blouin,  Louise Boulet,  Bernard Côté,  Richard Frenette,  Mario Girard,  Daniel Guay,  Zheng Huang,  Thomas R Jones,  France Laliberté,  Joseph J Lynch,  Joseph Mancini,  Evelyn Martins,  Paul Masson,  Eric Muise,  Douglas J Pon,  Peter K S Siegl,  Angela Styhler,  Nancy N Tsou,  Mervyn J Turner,  Robert N Young,  Yves Girard
Affiliations

Affiliation

  • 1 Department of Biology and Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Quebec, H9R 4P8, Canada. rick_friesen@merck.com
PMID: 12773045 DOI: 10.1021/jm0204542
Abstract

A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) Potassium Channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG Potassium Channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.

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