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

Journal of Pharmacology and Experimental Therapeutics

Volumn 330, Issue 3, 2009, Pages 922-931

  Davis, T Gregg ^a   Peterson, John J ^a   Kou, Jen Pyng ^a   Capper Spudich, Elizabeth A ^a   Ball, Doug ^b   Nials, Anthony T ^b   Wiseman, Joanne ^b   Solanke, Yemisi E ^b   Lucas, Fiona S ^b   Williamson, Richard A ^b   Ferrari, Livia ^a   Wren, Paul ^a   Knowles, Richard G ^b   Barnette, Mary S ^a   Podolin, Patricia L ^a  

^a GLAXOSMITHKLINE   (United States)

^b Mail Code UW2532 ^*

Author keywords

[No Author keywords available]

Indexed keywords

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; ALPHA 2 ADRENERGIC RECEPTOR; CILOMILAST; PHOSPHODIESTERASE 4A; PHOSPHODIESTERASE 4B2B; PHOSPHODIESTERASE 4C; PHOSPHODIESTERASE 4D3A; PHOSPHODIESTERASE I; PHOSPHODIESTERASE III; PHOSPHODIESTERASE IV; PHOSPHODIESTERASE IV INHIBITOR; PHOSPHODIESTERASE V; PHOSPHODIESTERASE VI; PHOSPHODIESTERASE VII; ROFLUMILAST; ROLIPRAM; SPLEEN EXONUCLEASE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CONTROLLED STUDY; CYTOKINE PRODUCTION; DOSE RESPONSE; DRUG DOSE ESCALATION; DRUG POTENCY; DRUG SELECTIVITY; FERRET; GASTROINTESTINAL TRACT; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; IN VIVO STUDY; MALE; MEASUREMENT; MOUSE; NEUTROPHILIA; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PICA; PRIORITY JOURNAL; PULMONARY NEUTROPHILIA; RAT; RESPIRATORY TRACT INFLAMMATION; STRESS; VOMITING;

AMINOPYRIDINES; ANIMALS; BENZAMIDES; CARBOXYLIC ACIDS; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 4; CYCLOPROPANES; FERRETS; HUMANS; LIPOPOLYSACCHARIDES; MICE; MICE, INBRED C57BL; NEUTROPHILS; NITRILES; PHOSPHODIESTERASE INHIBITORS; PICA; PIPERAZINES; PYRIDINES; RATS; RATS, INBRED LEW; RECEPTORS, ADRENERGIC, ALPHA-2; ROLIPRAM; TUMOR NECROSIS FACTOR-ALPHA; VOMITING;

EID: 70349109687     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.109.152454     Document Type: Article

References (27)

1. Albert A and Anderson JA (1984) On the existence of maximum likelihood estimates in logistic regression models. Biometrika 71:1-10.
2. Barnette MS, Grous M, Cieslinski LB, Burman M, Christensen SB, and Torphy TJ (1995) Inhibitors of phosphodiesterase IV (PDE IV) increase acid secretion in rabbit isolated gastric glands: correlation between function and interaction with a high-affinity rolipram binding site. J Pharmacol Exp Ther 273:1396-1402.
3. Borison HL, Borison R, and McCarthy LE (1981) Phylogenic and neurologic aspects of the vomiting process. J Clin Pharmacol 21:23S-29S.
4. Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, and Beume R (2001) In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther 297:280-290. (Pubitemid 32242588)
5. Burnouf C and Pruniaux MP (2002) Recent advances in PDE4 inhibitors as immunoregulators and anti-inflammatory drugs. Curr Pharm Des 8:1255-1296. (Pubitemid 34594253)
6. Compton CH, Gubb J, Nieman R, Edelson J, Amit O, Bakst A, Ayres JG, Creemers JP, Schultze-Werninghaus G, Brambilla C, et al. (2001) Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet 358:265-270. (Pubitemid 32738964)
7. Draheim R, Egerland U, and Rundfeldt C (2004) Anti-inflammatory potential of the selective phosphodiesterase 4 inhibitor N-(3,5-dichloro-pyrid-4-yl)-[1- (4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281), in human cell preparations. J Pharmacol Exp Ther 308:555-563. (Pubitemid 38134217)
8. Hatzelmann A and Schudt C (2001) Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 297:267-279. (Pubitemid 32242587)
9. Huet S, Bouvier A, Gruet M-A, and Jolivet E (1996) Statistical Tools for Nonlinear Regression - A Practical Guide with S-PLUS Examples, Springer-Verlag, New York.
10. Jin SL and Conti M (2002) Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-α responses. Proc Natl Acad Sci U S A 99:7628-7633.
11. Jin SL, Richard FJ, Kuo WP, D'Ercole AJ, and Conti M (1999) Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice. Proc Natl Acad Sci U S A 96:11998-12003.
12. King GL (1988) Animal models in the study of vomiting. Can J Physiol Pharmacol 68:260-268.
13. Lipworth BJ (2005) Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 365:167-175. (Pubitemid 40091808)
14. Mishell BB and Shiigi SM (1980) Selected Methods in Cellular Immunology, W.H. Freeman, San Francisco.
15. Mitchell D, Wells C, Hoch N, Lind K, Woods SC, and Mitchell LK (1976) Poison induced pica in rats. Physiol Behav 17:691-697.
16. Nagelkerke NJ (1991) A note on a general definition of the coefficient of determination. Biometrika 78:691-692.
17. Neter J and Wasserman W (1974) Applied Linear Statistical Models, Richard D. Irwin, Inc., Homewood, IL.
18. Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbröker D, and Bethke TD (2005) Roflumilast - an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 366:563-571. (Pubitemid 41140331)
19. Robichaud A, Stamatiou PB, Jin SL, Lachance N, MacDonald D, Laliberté F, Liu S, Huang Z, Conti M, and Chan CC (2002) Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest 110:1045-1052.
20. Robichaud A, Tattersall FD, Choudhury I, and Rodger IW (1999) Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret. Neuropharmacology 38:289-297. (Pubitemid 29073550)
21. Souness JE and Rao S (1997) Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal 9:227-236.
22. Spina D (2004) The potential of PDE4 inhibitors in respiratory disease. Curr Drug Targets Inflamm Allergy 3:231-236. (Pubitemid 39206651)
23. Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A, and Matsunaga T (1995a) Neuropharmacological mechanisms of emesis. I. Effects of antiemetic drugs on motion- and apomorphine-induced pica in rats. Methods Find Exp Clin Pharmacol 17:589-596. (Pubitemid 26029813)
24. Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A, and Matsunaga T (1995b) Neuropharmacological mechanisms of emesis. II. Effects of antiemetic drugs on cisplatin-induced pica in rats. Methods Find Exp Clin Pharmacol 17:647-652. (Pubitemid 26054642)
25. Takeda N, Hasegawa S, Morita M, and Matsunaga T (1993) Pica in rats is analogous to emesis: an animal model in emesis research. Pharmacol Biochem Behav 45:817-821. (Pubitemid 23213107)
26. Torphy TJ (1998) Phosphodiesterase isozymes. Molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 157:351-370.
27. Vignola AM (2004) PDE4 inhibitors in COPD - a more selective approach to treatment. Respir Med 98:495-503.