Selective Type IV Phosphodiesterase Inhibitors as Antiasthmatic Agents. The Syntheses and Biological Activities of 3-(Cyclopentyloxy)-4-methoxybenzamides and Analogs

The syntheses and biological activities of a number of benzamide derivatives, designed from rolipram, which are selective inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), are described. The effects of changes to the alkoxy groups, amide linkage, and benzamide N-phenyl ring on the inhibi...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 1994-05, Vol.37 (11), p.1696-1703
Main Authors: Ashton, Michael J, Cook, David C, Fenton, Garry, Karlsson, Jan-Anders, Palfreyman, Malcolm N, Raeburn, David, Ratcliffe, Andrew J, Souness, John E, Thurairatnam, Suga, Vicker, Nigel
Format: Article
Language:English
Subjects:
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
Animals
Aorta - enzymology
Asthma - drug therapy
Benzamides - chemical synthesis
Benzamides - pharmacology
Benzamides - therapeutic use
Bronchial Spasm - chemically induced
Bronchial Spasm - drug therapy
Chemistry
Eosinophils - drug effects
Eosinophils - metabolism
Exact sciences and technology
Guinea Pigs
Histamine - pharmacology
Isoenzymes - antagonists & inhibitors
Kinetics
Male
Molecular Structure
Noncondensed benzenic compounds
Organic chemistry
Phosphodiesterase Inhibitors - chemical synthesis
Phosphodiesterase Inhibitors - pharmacology
Preparations and properties
Pyridines - chemical synthesis
Pyridines - pharmacology
Pyridines - therapeutic use
Structure-Activity Relationship
Superoxides - metabolism
Swine
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The syntheses and biological activities of a number of benzamide derivatives, designed from rolipram, which are selective inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), are described. The effects of changes to the alkoxy groups, amide linkage, and benzamide N-phenyl ring on the inhibition of the cytosolic PDE IV from pig aorta have been investigated. As a result, some highly potent and selective PDE IV inhibitors have been identified. The most potent compounds have been further evaluated for their inhibitory potencies against PDE IV obtained from and superoxide O2- generation from guinea pig eosinophils in vitro. Selected compounds have also been examined for their activities in inhibiting histamine-induced bronchospasm in anaesthetized guinea pigs. 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (15j) showed exceptional potency in all tests and may have therapeutic potential in the treatment of asthma.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00037a021