Relaxant activity of 6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carboxamides and -thiocarboxamides and their analogs in guinea pig trachealis

Abstract

Structural modifications of the potassium channel activator cromakalim (1) are described in which the amide moiety at C-4 has been replaced by carboxamide and thiocarboxamide functions. Analogues in which the hydroxyl group at C-3 has been oxidized or removed are also disclosed. Such analogues display an interesting profile of smooth muscle relaxant activity in the guinea pig isolated trachea, not all of which appears to result from the opening of potassium channels, but few compounds retain useful in vivo activity. However, one compound in particular, 6-cyano-2,2-dimethyl-N-methyl-2H-1-benzopyran-4-thiocarboxamide (13) was shown to be a potent potassium channel activator in vitro and to provide prolonged protection to guinea pigs from the respiratory effects of inhaled histamine.

Cardioselective Antiischemic ATP-Sensitive Potassium Channel Openers. 2. Structure-Activity Studies on Benzopyranylcyanoguanidines; Modification of the Benzopyran Ring

“…Further, we have shown that such agents (e.g., BMS-180448) can protect the ischemic myocardium without hemodynamic changes,9-16 thus validating the selectivity data in vitro. These types of cardiac Scheme Ia 32b (10,11) 32c (12,13) 32d (15,16) 32e (17,18) 32f (23,24) 32g (25,26) 32h ( 27) 32i (28, 29) 32J (30, 31) a Numbers in parentheses correspond to the products prepared from 32; for R'-R3, X, and Y, see Table 1.…”

“…Preischemia or predrug contractile function, heart rate (HR), and coronary flow (extracorporeal electromagnetic flow probe; Carolina Medical Electronics, King, NC) were measured. The hearts were pretreated with vehicle (0.04% dimethyl sulfoxide, DMSO) or 1-30 µ test compound (except 18 which was tested up to 200 µ ) (n = 4/group). The respective drug or vehicle treatment was continued for 10 min prior to the initiation of ischemia, and the agents were administered as a solution in the perfusate.…”

Cardioselective anti-ischemic ATP-sensitive potassium channel openers

“…Therefore, further efforts were devoted to preparing the substituted analogs 15-17 of 12 with the aim of suppressing its metabolism via 4-hydroxylation. While similar in vasorelaxant potencies, the 4-chloro (15) and 4-fluoro (16) analogs showed slightly improved anti-ischemic potencies over 12. The 4-(trifluoromethyl) analog 17 was less active than 12 in both assays.…”

“…The urea (10) and thiourea (11) analogs were prepared according to published procedures. 15 Supplementary Material Available: Experimental procedures and spectral data for 5-8,12-19 and procedures for the biological assays (8 pages). Ordering information is given on any current masthead page.…”