Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294.
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.
Gale
Donna D
DD
Purdue Research Center, 444 Sawmill River Road, Ardsley, NY 10502, USA.
Hofer
Peter
P
Spina
Domenico
D
Seeds
Esther A
EA
Banner
Katherine H
KH
Harrison
Selina
S
Douglas
Gary
G
Matsumoto
Tatsui
T
Page
Clive P
CP
Wong
Richard H
RH
Jordan
Stephan
S
Smith
Forrest
F
Banik
Nandini
N
Halushka
Perry V
PV
Cavalla
David
D
Rotshteyn
Yakov
Y
Kyle
Donald J
DJ
Burch
Ronald M
RM
Chasin
Mark
M
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
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