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

Abstract

The ATP-sensitive potassium channel (KATP) openers are of considerable interest as myocardial protecting agents. However, there exists a narrow window of safety for the use of first-generation compounds as antiischemic agents due to their powerful peripheral vasodilating effects, which can result in underperfusion of the area already at risk. We have recently disclosed the discovery of benzopyranylcyanoguanidine type KATP openers (BMS-180448) which are more selective for the ischemic myocardium compared to the first-generation compounds. This publication deals with structure-activity relationships for the antiischemic activity of the lead compound 8. The presence of an electron-withdrawing group at C6, an sp3 center at C4, and a gem-dimethyl group at C2 appears to be essential for antiischemic activity. Cyanoguanidine can be replaced with a urea moiety. The results reported here support the hypothesis that distinct structure-activity relationships exist for antiischemic and vasorelaxant activities of compounds related to 8 and cromakalim. The trifluoromethyl analog 10 is 550-fold more selective in vitro for the ischemic myocardium compared to the first-generation agent cromakalim. The reasons for the selectivity of these compounds for the ischemic myocardium are not clear at the present time. They may be related to the existence of receptor subtypes in smooth muscle and the myocardium.

JTV-506, a new KATP channel opener, relaxes pulmonary artery isolated from monocrotaline-treated pulmonary hypertensive rats

“…It is speculated that the two methoxymethyl groups play an important role in coronary selective action [13]. Atwal et al [28] also reported a series of compounds with a benzopyran ring that have cardioselective actions. The benzopyranylcyanoguanidine type K ATP channel opener has antiischemic efficacy in animal models of myocardial ischemia without an effect on peripheral hemodynamic variables.…”

Second-Generation KATP Channel Openers

“…(3)) was the first cardioselective KCO [42]. Starting from BMS-180448 Atwal et al [43][44][45][46][47] performed detailed SAR studies (Fig. 4).…”

“…4). Among benzopyran ring modifications [43], an exchange of the oxygen in 1-position by CH 2 is tolerated; exchange by NH is detrimental. The geminal 2-methyl groups are essential.…”

Synthesis of 3-methoxy-6-phenyl-6, 6a-dihydro-[1] benzopyrano- [3, 4-b] [1] benzopyran.

“…These compounds can be used in many industrial applications such as light sensitive sunglasses [3,4], molecular electronics [5], optical memories [6][7][8][9]. On the other hand, many natural naphtho-and benzopyrans exhibit pharmacological applications [10,11] such as anti-HIV [12], antihypertensive [13] and anti-ischaemic [14] properties.…”