title: Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294.
abstract: V11294 is a new cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor of the rolipram class. In this report we present the pharmacological profile of V11294. V11294 inhibited PDE4 isolated from human lung with IC(50) 405 nM, compared to 3700 nM for rolipram. In contrast, V11294 inhibition of human PDE3 and PDE5 occurred only at concentrations greater than 100,000 nM. Like rolipram, V11294 inhibited PDE4D more potently than other PDE4 subtypes. V11294, when incubated with human anticoagulated whole blood in vitro, or administered to mice, caused increased cAMP concentration, consistent with inhibition of PDE4. V11294 inhibited lectin-induced proliferation and lipopolysaccharide-induced TNFalpha synthesis by human adherent monocytes in vitro and inhibited lipopolysaccharide-induced TNFalpha synthesis in mice. V11294 caused relaxation of guinea pig isolated trachea and inhibited allergen-induced bronchoconstriction and eosinophilia in guinea pigs at doses of 1 and 3 mg/kg, p.o. In ferrets, V11294 was not emetogenic at doses up to 30 mg/kg, p.o., despite plasma concentration reaching 10-fold the IC(50) for PDE4. In contrast, rolipram induced severe retching and vomiting at 10 mg/kg, p.o. In conclusion, V11294 is an orally active PDE4 inhibitor that exhibits antiinflammatory activity in vitro, and in vivo at doses that are not emetogenic.
authors.affiliation: Purdue Research Center, 444 Sawmill River Road, Ardsley, NY 10502, USA.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Gale
authors.forename: Peter
authors.initials: P
authors.lastname: Hofer
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
authors.forename: Esther A
authors.initials: EA
authors.lastname: Seeds
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Banner
authors.forename: Selina
authors.initials: S
authors.lastname: Harrison
authors.forename: Gary
authors.initials: G
authors.lastname: Douglas
authors.forename: Tatsui
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Clive P
authors.initials: CP
authors.lastname: Page
authors.forename: Richard H
authors.initials: RH
authors.lastname: Wong
authors.forename: Stephan
authors.initials: S
authors.lastname: Jordan
authors.forename: Forrest
authors.initials: F
authors.lastname: Smith
authors.forename: Nandini
authors.initials: N
authors.lastname: Banik
authors.forename: Perry V
authors.initials: PV
authors.lastname: Halushka
authors.forename: David
authors.initials: D
authors.lastname: Cavalla
authors.forename: Yakov
authors.initials: Y
authors.lastname: Rotshteyn
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Kyle
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Burch
authors.forename: Mark
authors.initials: M
authors.lastname: Chasin
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000818:Animals; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000378:metabolism; D011687:Purines / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D020889:Rolipram / Q000009:adverse effects / Q000097:blood / Q000378:metabolism
chemical_list: C465284:3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine; D010726:Phosphodiesterase Inhibitors; D011687:Purines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human; D020889:Rolipram