Novel selective PDE IV inhibitors as antiasthmatic agents. Synthesis and biological activities of a series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans.
A series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans have been synthesized and evaluated for their ability to selectively inhibit PDE IV isolated from guinea pig. Replacement of the 1-phenyl ring by a pyridone ring led to marked improvement of their selectivity for PDE IV over PDE III. The compounds that were most potent and selective involved those bearing an N-alkylpyridone ring at C-1. These compounds also showed potent antispasmogenic activity without causing significant changes in heart rate in the guinea pig. The most potent compound was 6,7-diethoxy-2, 3-bis(hydroxymethyl)-1-[1-(2-methoxyethyl)-2-oxo-pyrid-4-yl]nap hth alene (17f), ED50 values of histamine-induced and antigen-induced bronchoconstriction in the guinea pig being 0.08 and 2.3 mg/kg iv, respectively. This compound was chosen as a candidate for further pharmacological evaluation.
Iwasaki
T
T
Lead Optimization Research Laboratory, Tanàbe Seiyaku Company, Ltd., Osaka, Japan.
Kondo
K
K
Kuroda
T
T
Moritani
Y
Y
Yamagata
S
S
Sugiura
M
M
Kikkawa
H
H
Kaminuma
O
O
Ikezawa
K
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D017705:Lignans / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology*; D010276:Parasympatholytics / Q000138:chemical synthesis / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases; D013329:Structure-Activity Relationship
D018927:Anti-Asthmatic Agents; D017705:Lignans; D009281:Naphthalenes; D010276:Parasympatholytics; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4