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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.
J Pharmacol Exp Ther. 2009 Sep; 330(3):922-31.JP

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.

Authors+Show Affiliations

Respiratory Center of Excellence for Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19498103

Citation

Davis, T Gregg, et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 330, no. 3, 2009, pp. 922-31.
Davis TG, Peterson JJ, Kou JP, et al. 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. J Pharmacol Exp Ther. 2009;330(3):922-31.
Davis, T. G., Peterson, J. J., Kou, J. P., Capper-Spudich, E. A., Ball, D., Nials, A. T., Wiseman, J., Solanke, Y. E., Lucas, F. S., Williamson, R. A., Ferrari, L., Wren, P., Knowles, R. G., Barnette, M. S., & Podolin, P. L. (2009). 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. The Journal of Pharmacology and Experimental Therapeutics, 330(3), 922-31. https://doi.org/10.1124/jpet.109.152454
Davis TG, et al. 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. J Pharmacol Exp Ther. 2009;330(3):922-31. PubMed PMID: 19498103.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Davis,T Gregg, AU - Peterson,John J, AU - Kou,Jen-Pyng, AU - Capper-Spudich,Elizabeth A, AU - Ball,Doug, AU - Nials,Anthony T, AU - Wiseman,Joanne, AU - Solanke,Yemisi E, AU - Lucas,Fiona S, AU - Williamson,Richard A, AU - Ferrari,Livia, AU - Wren,Paul, AU - Knowles,Richard G, AU - Barnette,Mary S, AU - Podolin,Patricia L, Y1 - 2009/06/04/ PY - 2009/6/6/entrez PY - 2009/6/6/pubmed PY - 2009/9/22/medline SP - 922 EP - 31 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 330 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/19498103/The_identification_of_a_novel_phosphodiesterase_4_inhibitor_1_ethyl_5_{5_[_4_methyl_1_piperazinyl_methyl]_134_oxadiazol_2_yl}_N__tetrahydro_2H_pyran_4_yl__1H_pyrazolo[34_b]pyridin_4_amine__EPPA_1__with_improved_therapeutic_index_using_pica_feeding_in_rats_as_a_measure_of_emetogenicity_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=19498103 DB - PRIME DP - Unbound Medicine ER -