Cardiac-slowing amidines containing the 3-thioindone group. Potential antianginal agents.
A series of 3-thioindolamidines (and 3-indolamidines) related to mixidine (1) was studied for cardiac-slowing properties, following the discovery of activity for prototype thioindole 2. Structure-activity relationships were explored, leading to many potent antitachycardiac agents (6-9, 12, 13, 15-17, 20, 23, 24, 30, 34, 35, 45, and 47-49). Relative to 2, cardiac-slowing activity is enhanced by substitution of the indole nitrogen with small (C1-C3) saturated alkyl groups (6-9), unsaturated alkyl groups (12, 13, and 15-17), or a methoxyethyl group (20); replacement of the N-methyl group with alkyl (23) or phenyl groups (24); and extension of the ethylene bridge by two methylene units (34). Dethio (i.e., 3-indole) analogues of 2 with alkyl substitution on the indole nitrogen (47-49) have greater activity as well. Several potent compounds were also found to have minimal myocardial depression (6-9, 13, 45, and 47). Secondary pharmacological testing is reported for thioindoles 2, 6, 7, 9, and 28.
D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology; D000628:Aminophylline / Q000494:pharmacology; D000787:Angina Pectoris / Q000517:prevention & control*; D000818:Animals; D001561:Benzilates / Q000494:pharmacology; D001681:Biological Assay; D004285:Dogs; D005934:Glucagon / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013610:Tachycardia / Q000188:drug therapy
D000578:Amidines; D001561:Benzilates; D007202:Indicators and Reagents; D007211:Indoles; D000628:Aminophylline; C100295:poldine; D005934:Glucagon