title: 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.
authors.affiliation: Respiratory Center of Excellence for Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
authors.forename: T Gregg
authors.initials: TG
authors.lastname: Davis
authors.forename: John J
authors.initials: JJ
authors.lastname: Peterson
authors.forename: Jen-Pyng
authors.initials: JP
authors.lastname: Kou
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Capper-Spudich
authors.forename: Doug
authors.initials: D
authors.lastname: Ball
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Nials
authors.forename: Joanne
authors.initials: J
authors.lastname: Wiseman
authors.forename: Yemisi E
authors.initials: YE
authors.lastname: Solanke
authors.forename: Fiona S
authors.initials: FS
authors.lastname: Lucas
authors.forename: Richard A
authors.initials: RA
authors.lastname: Williamson
authors.forename: Livia
authors.initials: L
authors.lastname: Ferrari
authors.forename: Paul
authors.initials: P
authors.lastname: Wren
authors.forename: Richard G
authors.initials: RG
authors.lastname: Knowles
authors.forename: Mary S
authors.initials: MS
authors.lastname: Barnette
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Podolin
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes / Q000494:pharmacology; D005289:Ferrets; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010842:Pica / Q000139:chemically induced / Q000523:psychology*; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology; D020889:Rolipram / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014839:Vomiting / Q000139:chemically induced*
chemical_list: C543532:1-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; D000631:Aminopyridines; D001549:Benzamides; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes; D008070:Lipopolysaccharides; D009570:Nitriles; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011725:Pyridines; D018341:Receptors, Adrenergic, alpha-2; D014409:Tumor Necrosis Factor-alpha; C424423:Roflumilast; C433247:Cilomilast; D020889:Rolipram