Synthesis and antihypertensive activity of pyran oxygen and amide nitrogen replacement analogs of the potassium channel activator cromakalim

Abstract

The synthesis and oral antihypertensive activity in conscious spontaneously hypertensive rats of two new series of compounds related to the prototype potassium channel activator cromakalim (1) are described. In the first series, replacement of the benzopyran oxygen atom by nitrogen or methylene led to the 1,2,3,4-tetrahydroquinoline 12 and 1,2,3,4-tetrahydronaphthalene 13, which were both less active than 1. However, in contrast to the equivalent activity found previously for 1 and its dehydrated analogue 28, the dihydronaphthalene 27 was found to be more active than 13. In the second series, replacement of the C(4) amide nitrogen atom in acyclic amides related to cromakalim by methylene gave ketone 16 that was less active than the corresponding amide 15. However, replacement of the 4-acetonyl substituent in 16 by N,N-dimethylacetamido as in compound 22 resulted in a marked enhancement in activity. The compounds described in this paper thus illustrate the importance of the benzopyran oxygen and C(4) substituent on antihypertensive activity in the cromakalim series of potassium channel activators.

Cardioselective Anti-Ischemic ATP-Sensitive Potassium Channel Openers. 3. Structure-Activity Studies on Benzopyranyl Cyanoguanidines; Modification of the Cyanoguanidine Portion

“…12'15 In this study we also included the anti-inflammatory agent meclofenamic acid, which has previously been shown to inhibit the cardioprotective effects of Katp openers such as cromakalim (1), presumably by blocking Katp -16 The effect of Katp blockers on the increase in time to contracture induced by 30 µ of 13 (BMS-189365) is shown in Figure 2 glyburide (GLY, 0.1 µ ), and meclofenamic acid (MECLO, 5.0 µ ) on the increase in time to contracture by 30 µ BMS-189365 (13) in isolated perfused rat hearts. All three agents abolish the increase in time to contracture induced by 13. * = Significantly different from vehicle treated hearts; f = significantly different from hearts treated with BMS-189365 (13).…”

“…Replacment of the phenyl with a methyl group (12) retains anti-ischemic potency but not without the loss of cardiac selectivity. The bulky isoamyl replacement (13) for the phenyl ring of 3 yields a compound that is less potent than the lead compound 3. These results suggest that the phenyl ring may be optimal for good anti-ischemic activity and cardiac selectivity.…”

“…Previous studies have shown that the vasorelaxant and anti-ischemic effects of this series of compounds are inhibited by the Katp blocker glyburide, indicating that Katp opening is involved in their mechanism of action.512 To further support a Katp opening mechanism for the anti-ischemic actions of these compounds, we studied the effect of two structurally different blockers of Katp (glyburide, sodium 5-hydroxydecanoate) on the cardioprotective effects of 13 (BMS-189365) as measured by the increase in time to contracture in isolated perfused rat hearts. We chose to study compound 13 since previous studies by other workers have shown that cardioprotective effects of this compound in rabbit hearts are not affected by cotreatment with glyburide.14 The concentrations of the blockers used, while having no effect of their own on the time to the onset of contracture, have been previously shown to inhibit the cardioprotective effects of a variety of structurally different Katp openers (1,2) in rat hearts. 12'15 In this study we also included the anti-inflammatory agent meclofenamic acid, which has previously been shown to inhibit the cardioprotective effects of Katp openers such as cromakalim (1), presumably by blocking Katp -16 The effect of Katp blockers on the increase in time to contracture induced by 30 µ of 13 (BMS-189365) is shown in Figure 2 glyburide (GLY, 0.1 µ ), and meclofenamic acid (MECLO, 5.0 µ ) on the increase in time to contracture by 30 µ BMS-189365 (13) in isolated perfused rat hearts.…”

ATP-Sensitive Potassium Channel Openers and 2,3-Dimethyl-2-Butylamine Derivatives

“…Almansa et al synthesized a series of 2,2-dialkyltetralin-1-ketone derivatives by replacing the oxygen atom with a carbonyl group, producing by screening UR28225 (7), a compound that constricts and inhibits portal vein and bronchus smooth muscle [47], which are similar to that of compound (1). In addition, substituting -O-with -CH-, -NR- [48], -S-, -SO-, or -SO 2 -in the 1-position [49] produces compounds with some bioactivity, although these compounds have a lower antihypertensive effect than compound (1). This indicates the significance of benzopyran mother nucleus for bioactivity.…”

An overview of recent advances in the catalytic synthesis of substituted pyrans

“…Pyran derivatives are found in several natural products and pharmaceutical compounds. [ 6 ] They have an array of profound biological activities, namely, Chk1 kinase inhibitory, [ 7 ] analgesic, [ 8 ] anticancer, [ 9 ] vasodilatory, [ 10 ] antihypertensive, [ 11 ] hepatoprotective, [ 12 ] cardiotonic, [ 13 ] spasmolytic, [ 14 ] antileukemia, [ 15 ] antiallergic, [ 16 ] anaphylactic, [ 17 ] anti‐Alzheimer, [ 18 ] diuretic, [ 19 ] antimicrobial, [ 20–22 ] antioxidant, [ 22 ] and antiproliferative [ 23 ] . Furthermore, they are important building blocks in organic synthesis.…”