title: 7-Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridines as novel inhibitors of human eosinophil phosphodiesterase.
abstract: High-throughput file screening against inhibition of human lung PDE4 led to the discovery of 3-ethyl-1-(4-fluorophenyl)-6-phenyl-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent than 11 with IC50 values of 0.03-1.6 microM. One such compound, CP-220,629 (22) (IC50 = 0.44 microM), was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 2.0 mg/kg, po) and demonstrated a significant reduction in eosinophil (55%), neutrophil (65%), and IL-1beta (82%) responses to antigen challenge in atopic monkeys (10 mg/kg, po).
authors.affiliation: Central Research Division, Pfizer Inc, Groton, Connecticut 06340, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Duplantier
authors.forename: C J
authors.initials: CJ
authors.lastname: Andresen
authors.forename: J B
authors.initials: JB
authors.lastname: Cheng
authors.forename: V L
authors.initials: VL
authors.lastname: Cohan
authors.forename: C
authors.initials: C
authors.lastname: Decker
authors.forename: F M
authors.initials: FM
authors.lastname: DiCapua
authors.forename: K G
authors.initials: KG
authors.lastname: Kraus
authors.forename: K L
authors.initials: KL
authors.lastname: Johnson
authors.forename: C R
authors.initials: CR
authors.lastname: Turner
authors.forename: J P
authors.initials: JP
authors.lastname: UmLand
authors.forename: J W
authors.initials: JW
authors.lastname: Watson
authors.forename: R T
authors.initials: RT
authors.lastname: Wester
authors.forename: A S
authors.initials: AS
authors.lastname: Williams
authors.forename: J A
authors.initials: JA
authors.lastname: Williams
mesh_terms: D000402:Airway Obstruction / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002452:Cell Count / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004804:Eosinophils / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D008968:Molecular Conformation; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D013329:Structure-Activity Relationship
chemical_list: D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004095:Dihydropyridines; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011760:Pyrrolidinones; D010047:Ovalbumin; C112863:CP 220629; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D020889:Rolipram