title: 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.
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.
authors.affiliation: 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
authors.forename: Richard W
authors.initials: RW
authors.lastname: Friesen
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: Marc
authors.initials: M
authors.lastname: Blouin
authors.forename: Louise
authors.initials: L
authors.lastname: Boulet
authors.forename: Bernard
authors.initials: B
authors.lastname: Côté
authors.forename: Richard
authors.initials: R
authors.lastname: Frenette
authors.forename: Mario
authors.initials: M
authors.lastname: Girard
authors.forename: Daniel
authors.initials: D
authors.lastname: Guay
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Jones
authors.forename: France
authors.initials: F
authors.lastname: Laliberté
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Joseph
authors.initials: J
authors.lastname: Mancini
authors.forename: Evelyn
authors.initials: E
authors.lastname: Martins
authors.forename: Paul
authors.initials: P
authors.lastname: Masson
authors.forename: Eric
authors.initials: E
authors.lastname: Muise
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Pon
authors.forename: Peter K S
authors.initials: PK
authors.lastname: Siegl
authors.forename: Angela
authors.initials: A
authors.lastname: Styhler
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Tsou
authors.forename: Mervyn J
authors.initials: MJ
authors.lastname: Turner
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
authors.forename: Yves
authors.initials: Y
authors.lastname: Girard
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000438:Alcohols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D018360:Crystallography, X-Ray; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D012453:Saimiri; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000438:Alcohols; D003497:Cyclic N-Oxides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C475430:L 869298; D010726:Phosphodiesterase Inhibitors; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4