Angiotensin-converting enzyme inhibitors: new orally active 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones possessing antihypertensive activity

The preparation of a series of 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) in vitro and in vivo were examined. These compounds are assumed to act as prodrugs since they unde...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1986-05, Vol.29 (5), p.784-796
Main Authors: Skiles, Jerry W, Suh, John T, Williams, Bruce E, Menard, Paul R, Barton, Jeffrey N, Loev, Bernard, Jones, Howard, Neiss, Edward S, Schwab, Alfred
Format: Article
Language:English
Subjects:
Administration, Oral
Angiotensin-Converting Enzyme Inhibitors
Animals
Antihypertensive Agents - chemical synthesis
Antihypertensive Agents - therapeutic use
Chemistry
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms
Magnetic Resonance Spectroscopy
Mathematics
Organic chemistry
Preparations and properties
Rats
Structure-Activity Relationship
Thiazepines - chemical synthesis
Thiazepines - toxicity
Thiazines - chemical synthesis
Thiazines - toxicity
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Summary:The preparation of a series of 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) in vitro and in vivo were examined. These compounds are assumed to act as prodrugs since they undergo rapid ring-opening reactions to give the corresponding biologically active free SH compounds when incubated with rat plasma or when treated with aqueous 0.1 N HCl or phosphate buffer (pH 7.4). The thiazepines 23-25 and 30 are potent inhibitors of ACE when administered po to rats and are comparable in potency to captopril (1). The most active thiazines in rats, po, were 42 and 45. Of the benzothiazepines studied, 22a was the most active in inhibiting ACE in the conscious normotensive rat, ID50 = 0.15 mg/kg, po. The acute antihypertensive effects of oral administration of a number of these compounds on mean arterial pressure and heart rate were studied in spontaneously hypertensive rats (SHR) maintained on a sodium-deficient diet.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00155a032