7-Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridines as novel inhibitors of human eosinophil phosphodiesterase.
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).
Duplantier
A J
AJ
Central Research Division, Pfizer Inc, Groton, Connecticut 06340, USA.
Andresen
C J
CJ
Cheng
J B
JB
Cohan
V L
VL
Decker
C
C
DiCapua
F M
FM
Kraus
K G
KG
Johnson
K L
KL
Turner
C R
CR
UmLand
J P
JP
Watson
J W
JW
Wester
R T
RT
Williams
A S
AS
Williams
J A
JA
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
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