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The identification of a novel phosphodiesterase 4 inhibitor, 1-ethyl-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,3,4-oxadiazol-2-yl}-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (EPPA-1), with improved therapeutic index using pica feeding in rats as a measure of emetogenicity.

Abstract
Clinical utility of phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory agents has, to date, been limited by adverse effects including nausea and emesis, making accurate assessment of emetic versus anti-inflammatory potencies critical to the development of inhibitors with improved therapeutic indices. In the present study we determined the in vitro and in vivo anti-inflammatory potencies of the first-generation PDE4 inhibitor, rolipram, the second-generation inhibitors, roflumilast and cilomilast, and a novel third generation inhibitor, 1-ethyl-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,3,4-oxadiazol-2-yl}-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (EPPA-1). The rank-order potency against lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha production by human peripheral blood mononuclear cells was roflumilast (IC(50) = 5 nM) > EPPA-1 (38) > rolipram (269) > cilomilast (389), and against LPS-induced pulmonary neutrophilia in the rat was EPPA-1 (D(50) = 0.042 mg/kg) > roflumilast (0.24) > rolipram (3.34) > cilomilast (4.54). Pica, the consumption of non-nutritive substances in response to gastrointestinal stress, was used as a surrogate measure for emesis, giving a rank-order potency of rolipram (D(50) = 0.495 mg/kg) > roflumilast (1.6) > cilomilast (6.4) > EPPA-1 (24.3). The low and high emetogenic activities of EPPA-1 and rolipram, respectively, detected in the pica model were confirmed in a second surrogate model of emesis, reversal of alpha(2)-adrenoceptor-mediated anesthesia in the mouse. The rank order of therapeutic indices derived in the rat [(pica D(50))/(neutrophilia D(50))] was EPPA-1 (578) > roflumilast (6.4) > cilomilast (1.4) > rolipram (0.15), consistent with the rank order derived in the ferret [(emesis D(50))/(neutrophilia D(50))]. These data validate rat pica feeding as a surrogate for PDE4 inhibitor-induced emesis in higher species, and identify EPPA-1 as a novel PDE4 inhibitor with an improved therapeutic index.
AuthorsT Gregg Davis, John J Peterson, Jen-Pyng Kou, Elizabeth A Capper-Spudich, Doug Ball, Anthony T Nials, Joanne Wiseman, Yemisi E Solanke, Fiona S Lucas, Richard A Williamson, Livia Ferrari, Paul Wren, Richard G Knowles, Mary S Barnette, Patricia L Podolin
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 330 Issue 3 Pg. 922-31 (Sep 2009) ISSN: 1521-0103 [Electronic] United States
PMID19498103 (Publication Type: Journal Article)
Chemical References
  • 1-ethyl-5-(5-((4-methyl-1-piperazinyl)methyl)-1,3,4-oxadiazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo(3,4-b)pyridin-4-amine
  • Aminopyridines
  • Benzamides
  • Carboxylic Acids
  • Cyclohexanecarboxylic Acids
  • Cyclopropanes
  • Lipopolysaccharides
  • Nitriles
  • Phosphodiesterase 4 Inhibitors
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Pyridines
  • Receptors, Adrenergic, alpha-2
  • Tumor Necrosis Factor-alpha
  • Roflumilast
  • Cilomilast
  • Rolipram
Topics
  • Aminopyridines (pharmacology)
  • Animals
  • Benzamides (pharmacology)
  • Carboxylic Acids (pharmacology)
  • Cyclohexanecarboxylic Acids
  • Cyclopropanes (pharmacology)
  • Ferrets
  • Humans
  • Lipopolysaccharides (antagonists & inhibitors, toxicity)
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils (drug effects)
  • Nitriles (pharmacology)
  • Phosphodiesterase 4 Inhibitors
  • Phosphodiesterase Inhibitors (pharmacology)
  • Pica (chemically induced, psychology)
  • Piperazines (pharmacology)
  • Pyridines (pharmacology)
  • Rats
  • Rats, Inbred Lew
  • Receptors, Adrenergic, alpha-2 (drug effects, physiology)
  • Rolipram (pharmacology)
  • Tumor Necrosis Factor-alpha (antagonists & inhibitors)
  • Vomiting (chemically induced)

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