JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Aoki, M.
Right arrow Articles by Yamada, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aoki, M.
Right arrow Articles by Yamada, T.

Vol. 295, Issue 1, 255-260, October 2000

A Novel Phosphodiesterase Type 4 Inhibitor, YM976 (4-(3-Chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one), with Little Emetogenic Activity

Motonori Aoki, Miki Kobayashi, Jun Ishikawa, Yuji Saita, Yoshiya Terai, Kazuhisa Takayama , Keiji Miyata and Toshimitsu Yamada

Inflammation Research, Pharmacology Laboratories (M.A., M.K., J.I., Y.S., Y.T., K.T., K.M., T.Y.), Medicinal Chemistry Research II, Chemistry Laboratories (K.T.), Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki 305-8585, Japan

We synthesized a novel phosphodiesterase type 4 (PDE4) inhibitor, YM976, that is structurally different from the other PDE4 inhibitors like rolipram. In the present study, the pharmacological profile of YM976 was investigated. YM976 exhibited a strong and competitive inhibition against PDE4 purified from human peripheral leukocytes with an IC50 of 2.2 nM. IC50 values of rolipram and RP73401 were 820 and 0.43 nM, respectively. Test compounds had no effects on the other PDE isozymes, PDE1, -2, -3, and -5. YM976 potentiated prostaglandin E2-induced cAMP accumulation in a human mononuclear cell line, U937, and inhibited tumor necrosis factor-alpha production from human peripheral blood mononuclear cells stimulated by lipopolysaccharide. Anti-inflammatory activities of PDE4 inhibitors were compared in rat carrageenan-induced pleurisy models. YM976, rolipram, and RP73401 inhibited the cell infiltration into the pleural cavity with oral ED30 values of 9.1, 10, and 7.4 mg/kg, respectively. YM976 produced no emesis up to 10 mg/kg, whereas rolipram and RP73401 induced emesis at oral doses of 3 mg/kg. To evidence the dissociation of anti-inflammatory activity from emesis, the anti-inflammatory effect of YM976 was examined in ferrets. YM976 dose dependently reduced carrageenan-induced leukocyte infiltration at the doses of 1, 3, and 10 mg/kg, p.o. On the other hand, rolipram failed to show obvious inhibition at doses that do not induce emesis. In conclusion, YM976 is a novel and orally active PDE4 inhibitor and possesses a good separation of emetogenicity from anti-inflammatory activity.

0022-3565/00/2951-0255$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Biophys. JHome page
Y. Xiong, H.-T. Lu, Y. Li, G.-F. Yang, and C.-G. Zhan
Characterization of a Catalytic Ligand Bridging Metal Ions in Phosphodiesterases 4 and 5 by Molecular Dynamics Simulations and Hybrid Quantum Mechanical/Molecular Mechanical Calculations
Biophys. J., September 1, 2006; 91(5): 1858 - 1867.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
G. N. Dietsch, C. R. Dipalma, R. J. Eyre, T. Q. Pham, K. M. Poole, N. B. Pefaur, W. D. Welch, E. Trueblood, W. D. Kerns, and S. T. Kanaly
Characterization of the Inflammatory Response to a Highly Selective PDE4 Inhibitor in the Rat and the Identification of Biomarkers that Correlate with Toxicity
Toxicol Pathol, January 1, 2006; 34(1): 39 - 51.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
A. Trifilieff, D. Wyss, C. Walker, L. Mazzoni, and R. Hersperger
Pharmacological Profile of a Novel Phosphodiesterase 4 Inhibitor, 4-(8-Benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic Acid (NVP-ABE171), a 1,7-Naphthyridine Derivative, with Anti-Inflammatory Activities
J. Pharmacol. Exp. Ther., April 1, 2002; 301(1): 241 - 248.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. Aoki, M. Fukunaga, T. Sugimoto, Y. Hirano, M. Kobayashi, K. Honda, and T. Yamada
Studies on Mechanisms of Low Emetogenicity of YM976, a Novel Phosphodiesterase Type 4 Inhibitor
J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 1142 - 1149.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. Aoki, S. Yamamoto, M. Kobayashi, K. Ohga, H. Kanoh, K. Miyata, K. Honda, and T. Yamada
Antiasthmatic Effect of YM976, a Novel PDE4 Inhibitor, in Guinea Pigs
J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 165 - 173.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. Aoki, M. Fukunaga, M. Kitagawa, K. Hayashi, T. Morokata, G. Ishikawa, S. Kubo, and T. Yamada
Effect of a Novel Anti-Inflammatory Compound, YM976, on Antigen-Induced Eosinophil Infiltration into the Lungs in Rats, Mice, and Ferrets
J. Pharmacol. Exp. Ther., December 1, 2000; 295(3): 1149 - 1155.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics.