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

• Published in: Journal of medicinal chemistry Vol. 37; no. 11; pp. 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: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.05.1994; Amer Chemical Soc
• 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; Chemistry, Medicinal; Eosinophils - drug effects; Eosinophils - metabolism; Exact sciences and technology; Guinea Pigs; Histamine - pharmacology; Isoenzymes - antagonists & inhibitors; Kinetics; Life Sciences & Biomedicine; Male; Molecular Structure; Noncondensed benzenic compounds; Organic chemistry; Pharmacology & Pharmacy; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - pharmacology; Preparations and properties; Pyridines - chemical synthesis; Pyridines - pharmacology; Pyridines - therapeutic use; Science & Technology; Structure-Activity Relationship; Superoxides - metabolism; Swine; SMOOTH-MUSCLE; PHARMACOLOGY; ASTHMA; BUDESONIDE; AMP-SPECIFIC PHOSPHODIESTERASE; GUINEA-PIG; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; Non steroidal antiinflammatory agent; Ether; Structure activity relation; Chlorine Organic compounds; Bronchodilator; Carboxamide; Benzenic compound; Antiasthma agent; Pyridine derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00037a021

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 O-2(-) 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.