Orally active PDE4 inhibitors with therapeutic potential.
Based on the successful results in the clinical trial of Ariflo, further optimization of the spatial arrangement of the three pharmacophores (carboxylic acid moiety, nitrile moiety and 3-cyclopentyl-4-methoxyphenyl moiety) in the structure of Ariflo 1 was attempted using a bicyclo[3.3.0]octane template instead of a cyclohexane template. As a result, 2a, 7a and 7b were found to be orally active and were predicted to have an improved therapeutic potential based on evaluation by cross-species and same-species comparisons. Structure-activity relationships (SARs) of these compounds are also discussed.
Minase Research Institute, Ono Pharmaceutical Co. Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Hiroshi
H
Ochiai
Tazumi
T
Ohtani
Akiharu
A
Ishida
Katuya
K
Kishikawa
Takaaki
T
Obata
Hisao
H
Nakai
Masaaki
M
Toda
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D051381:Rats; D020298:U937 Cells
D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4