title: Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor.
abstract: The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. dwight_macdonald@merck.com
authors.forename: Dwight
authors.initials: D
authors.lastname: Macdonald
authors.forename: Anthony
authors.initials: A
authors.lastname: Mastracchio
authors.forename: Hélène
authors.initials: H
authors.lastname: Perrier
authors.forename: Daniel
authors.initials: D
authors.lastname: Dubé
authors.forename: Michel
authors.initials: M
authors.lastname: Gallant
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacombe
authors.forename: Denis
authors.initials: D
authors.lastname: Deschênes
authors.forename: Bruno
authors.initials: B
authors.lastname: Roy
authors.forename: John
authors.initials: J
authors.lastname: Scheigetz
authors.forename: Kevin
authors.initials: K
authors.lastname: Bateman
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Laird A
authors.initials: LA
authors.lastname: Trimble
authors.forename: Stephen
authors.initials: S
authors.lastname: Day
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nicoll-Griffith
authors.forename: Jose M
authors.initials: JM
authors.lastname: Silva
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: France
authors.initials: F
authors.lastname: Laliberté
authors.forename: Susana
authors.initials: S
authors.lastname: Liu
authors.forename: Diane
authors.initials: D
authors.lastname: Ethier
authors.forename: Doug
authors.initials: D
authors.lastname: Pon
authors.forename: Eric
authors.initials: E
authors.lastname: Muise
authors.forename: Louise
authors.initials: L
authors.lastname: Boulet
authors.forename: Chi Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Angela
authors.initials: A
authors.lastname: Styhler
authors.forename: Stella
authors.initials: S
authors.lastname: Charleson
authors.forename: Joseph
authors.initials: J
authors.lastname: Mancini
authors.forename: Paul
authors.initials: P
authors.lastname: Masson
authors.forename: David
authors.initials: D
authors.lastname: Claveau
authors.forename: Donald
authors.initials: D
authors.lastname: Nicholson
authors.forename: Mervyn
authors.initials: M
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*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D012453:Saimiri; D012756:Sheep; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced
chemical_list: C507187:L-454,560; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4