Antibronchoconstrictor activity of two new phosphodiesterase inhibitors, a triazolopyrazine (ICI 58 301) and a triazolopyrimidine (ICI 63 197)

Abstract

A triazolopyrazine (ICI 58 301) and a triazolopyrimidine (ICI 63 197), both potent inhibitors of 3'5'-cyclic adenosine monophosphate phosphodiesterase, protected conscious guinea-pigs against an otherwise lethal bronchospasm caused by inhalation of histamine. Both compounds were active when given by mouth and the activity was both rapid in onset and persistent. Bronchospasm caused by histamine or acetylcholine in guinea-pig isolated lungs was reduced when the lungs were perfused with dilute solutions of the compounds and the bronchodilator activity of catecholamines was potentiated.In anaesthetized animals the compounds were relatively more active against severe bronchospasm than against milder stimuli. The antibronchoconstrictor effects on conscious guinea-pigs were blocked by propranolol but not by practolol even in much larger doses. Propranolol did not, however, block the effect on the isolated lung. It appears possible that the antibronchoconstrictor activity is a manifestation of the inhibition of phosphodiesterase.A study of the pharmacological properties of purine isosteres, made in these laboratories during the past 15 years has revealed that two series of compounds, triazolopyrazines and triazolo-pyrimidines are particularly potent inhibitors of bronchospasm in guinea-pigs. The representatives of these series now discussed are 3-acetamido-6-methyl-8-n-propyl-s-triazolo [4,3-a] (Dukes, 1971). ICI 58 301 will be referred to as A and ICI 63 197 as B.

Microiontophoretic studies of the effects of cyclic nucleotides on excitability of neurones in the rat cerebral cortex

“…The blockade of 5' AMP has also been seen by Phillis & Kostopoulos (1975). It (Davies, 1973) causing, on balance, a reduction of acetylcholine responses.…”

Pharmacologic Intervention to Prevent Hemodialysis Vascular Access Thrombosis

“…Triazolopyridine is a pyridine com pound similar to dipyridamole that was originally studied as a phosphodiesterase inhibitor and bronchodilator [189]. It was eventually marketed as a smooth muscle vasodilator and antianginal agent in Japan.…”

On the action of combination bronchodilators

“…These results imply that the functional antagonists could not fully overcome a cholinergic component in the disease. As well, the future may see the development of potent phosphodiesterase inhibitors, such as ICI 58301 [72] or flavanoid compounds [73] for use in asthma therapy. Even very recent discoveries such as reproterol, a molecular combination of a phenylethylamine derivative and theophylline may play a role in specific asthma therapy to the demise of the established older medications (personal communication -Professor Dr W. Schumtzler, Aachen, FRG).…”