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

Abstract

ATP-sensitive potassium (K(ATP)) channels have important functions through their coupling of cellular energetic networks and their ability to decode metabolic signals, and they are implicated in diseases of many organs. K(ATP) channels are formed by the physical association between the inwardly rectifier potassium channels (Kir6.x) and the regulatory sulfonylurea receptor subunit (SUR), which form a hetero-octameric complex. Different subtypes of K(ATP) channels exist in various tissues. K(ATP) channel openers (KCOs) are classified into nine chemical families according to their molecular structures: (1) benzopyrans, (2) cyanoguanidines, (3) thioformamides, (4) pyrimidine derivatives, (5) pyridine derivatives, (6) benzothiadiazines, (7) dihydropyridines, (8) nicotinamide derivatives, and (9) aliphatic amines. Although the model also predicts that KCOs have four co-binding areas, it was hypothesized that the main contribution lies in the binding domain of hydrophobicity of the side chain. A series of compounds containing the skeleton of the aliphatic secondary amines as a side chain was designed. It was found that N-isopropyl 2,3-dimethyl-2-butylamine (iptakalim, 91) is a novel KCOs. Iptakalim regulates the pore selectively of the inwardly rectifier potassium channel and dilates smaller arteries, but has little effect on vasodilatation of the aorta. Iptakalim administered p.o. has selective and long-lasting antihypertensive effects in hypertensive animals and does not induce tolerance, but has little effect on blood pressure in normotensive animals. Meanwhile, it also reverses cardiovascular remodeling and protects the brain and kidney against damage caused by hypertension in animal models. Iptakalim is in phase II clinical trials now and has a promising future as a treatment for hypertension.

Natakalim Ameliorates Isoproterenol-Induced Chronic Heart Failure by Protecting against Endothelial Dysfunction

“…The SUR2B/Kir6.1 subtype is primarily found in the vascular endothelium [7] . Our previous studies had demonstrated that iptakalim, a new type of K ATP channel opener, can prevent the progression of cardiac hypertrophy to heart failure induced by pressure overload by activating the SUR2B/Kir6.1 channel subtype, thus protecting endothelium function [3,[8][9][10][11] . Natakalim, a novel SUR2B/Kir6.1-K ATP channel opener, is a derivative of iptakalim.…”

Iptakalim, an ATP-sensitive potassium channel opener, confers neuroprotection against cerebral ischemia/reperfusion injury in rats by protecting neurovascular unit cells

“…Moreover, iptakalim is a small water-soluble compound and has little difficulty crossing the blood-brain barrier. Long-term systemic administration has proven that it has minimal toxic side effects (Wang et al, 2007).…”

“…Iptakalim, a unique type of K ATP channel opener, exerts its neuroprotective effects by activating the sulfonylurea receptor 2 (SUR2), rather than the SUR1, type of K ATP channel, and is a promising antihypertensive drug for clinical use 2006;Wang et al, 2007). In addition, the whole cell patch clamp technique showed that iptakalim has a high affinity for neuronal K ATP channels in the brain .…”

Association of the antihypertensive response of iptakalim with KCNJ11 (Kir6.2 gene) polymorphisms in Chinese Han hypertensive patients

“…It can produce long-lasting hypotensive effects without tolerance. At the same time it exertes a protective effect against hypertensive damage to target organs [8][9][10][11][12][13][14][15] . Iptakalim is an effective and well tolerated antihypertensive drug.…”