New orally active PDE4 inhibitors with therapeutic potential.
The design, synthesis, and biological evaluation of a series of pyrazolopyridines was carried out. Structural optimization of the aniline moiety of 4-anilinopyrazolopyridine derivative 3a, which is one of the newly discovered chemical leads for PDE4 inhibitors from our in-house library, was performed successfully. The details of the discovery of new orally active PDE4 inhibitors, which are expected to show therapeutic potential, are presented and their structure-activity relationships are discussed. Pharmacological evaluation and pharmacokinetic data for representative compounds are also presented.
Ochiai
Hiroshi
H
Minase Research Institute, Ono Pharmaceutical Co. Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Ishida
Akiharu
A
Ohtani
Tazumi
T
Kusumi
Kensuke
K
Kishikawa
Katuya
K
Yamamoto
Susumu
S
Takeda
Hiroshi
H
Obata
Takaaki
T
Nakai
Hisao
H
Toda
Masaaki
M
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D001681:Biological Assay; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015195:Drug Design; D005289:Ferrets; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D020298:U937 Cells
D000814:Aniline Compounds; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C023650:aniline