Identification of pyridazino[4,5-b]indolizines as selective PDE4B inhibitors.
Substituted pyridazino[4,5-b]indolizines were identified as potent and selective PDE4B inhibitors. We describe the structure-activity relationships generated around an HTS hit that led to a series of compounds with low nanomolar affinity for PDE4B and high selectivity over the PDE4D subtype.
Donnell
Andrew F
AF
Worldwide Medicinal Chemistry, Pfizer Global Research and Development, CN 8000, Princeton, NJ 08543, USA. donnela@wyeth.com
Dollings
Paul J
PJ
Butera
John A
JA
Dietrich
Arlene J
AJ
Lipinski
Kerri K
KK
Ghavami
Afshin
A
Hirst
Warren D
WD
D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D006801:Humans; D007212:Indolizines / Q000737:chemistry* / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D007212:Indolizines; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4