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

被引：63

作者：

Friesen, RW

Ducharme, Y

Ball, RG

Blouin, M

Boulet, L

Côté, B

Frenette, R

Girard, M

Guay, D

Huang, Z

Jones, TR

Laliberté, F

Lynch, JJ

Mancini, J

Martins, E

Masson, P

Muise, E

Pon, DJ

Siegl, PKS

Styhler, A

Tsou, NN

Turner, MJ

Young, RN

Girard, Y

机构：

[1] Merck Frosst Ctr Therapeut Res, Dept Biol, Pointe Claire, PQ H9R 4P8, Canada

[2] Merck Frosst Ctr Therapeut Res, Dept Med Chem, Pointe Claire, PQ H9R 4P8, Canada

[3] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

[4] Merck Res Labs, Dept Pharmacol, W Point, PA 19486 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2003年 / 46卷 / 12期

关键词：

D O I：

10.1021/jm0204542

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：2413 / 2426

页数：14

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