Diazoxide, structure

Diazoxide (II) has been known since the early 1960 s (9.) and must be considered as a well known lead. It bears a structural resemblance to the diuretic agent, chlorothiazide (XIX) but, unlike chlorothiazide, it is non-diuretic. Analogs have been prepared by scientists at Schering (10) and by a group in Italy (11). The Italian group reported that compound XX lowers blood pressure and heart rate intravenously in rats but causes... 

The thiazide diuretics possess antihypertensive properties, in part consequent upon electrolyte and plasma-volume changes but mainly resulting from a direct cardiovascular depressant effect. This is clearly illustrated by the non-diuretic thiazide, diazoxide, which is an effective hypotensive [326b, c]. It is not therefore, surprising that both these properties should be found (in varying proportions) in other, structurally related, compounds. One particular line of research, aimed at modification of the thiazide heterocycle (the o-chlorobenzenesulphonamide moiety was untouched as it was believed essential to activity-the subsequent advent of ethacrynic acid questions this belieO examined first the corresponding... 

The single crystal X-ray structure of 3-methyl-4//-pyrido[2,3- ] l>2,4-thiadiazine 1,1,-dioxide 13 was compared to that of diazoxide 14 in order to determine the predominant tautomeric form and it was found that both these thiadiazine-dioxides exist in the AH tautomeric form in the solid state <1995AXG2064>. 

Despite these challenges, the area of K+ channel openers (PCOs) is emerging as an active area of drug design. Over the past 5-10 years, eight novel structural classes of PCOs have received systematic development benzopyrans (e.g., cromakalim, 7.27), cyanoguanidines (e.g., pinacidil, 7.28), thioformamides (e.g., aprikalim, 7.29), pyridyl nitrates (e.g., nicorandil, 7.30), benzothiadiazines (e.g., diazoxide, 7.31), pyrimidine sulphates (e.g., minoxidil sulphate, 7.32), tertiary carbinols, and dihydropyridines. These various classes have been subjected to analog preparation with compound optimization via structure-activity studies. 

In contrast to the structurally related thiazide diuretics, diazoxide causes renal salt and water retention. However, because the drug is used for short periods only, this is rarely a problem. 

The electronic structures of hydrochlorothiazide 146 and related substances have been determined by the complete neglect of differential overlap (CNDO/2) method (83AF688). The calculation confirms that the diuretic thiazides are electron-accepting, whereas diazoxide 147, a non-... 

This topic has been reviewed both generally [9], and specifically for variation in the benzopyran nucleus [10]. SARs have also formed part of several comprehensive and useful reports and reviews [11-15], while full details of lead and development KCAs are regularly updated in a useful compilation [16] devoted to modulators of K channels. Hence, this section will address recent advances, and those previously reported [9, 10], where further detail is now available. These are best presented in terms of the different series of KCAs based on the prototype molecules, cromakalim (1), RP 49356 (4), pinacidil (6), and nicorandil (7) that, together with the older compounds, minoxidil sulphate (8) and diazoxide (9), now recognized as KCAs, illustrate the widening range of structural types of this classification... 

Another example of how new chemical entities can be derived from compounds with unrelated biological effects is that of the development of the potassium channel agonist diazoxide (Fig. 2.29). This compound was developed as a result of the observation that the thiazide diuretics, such as chlorothiazide, not only had a diuretic component, because of inhibition of sodium absorption in the distal convoluted tubule, but also a direct effect on the renal vasculature. Structural modification to enhance this direct effect led to the development of diazoxide and related potassium channel agonists for the treatment of hypertension (see Chapter 29). 

Fig. 2.29. Structural similarity of chlorothiazide (a diuretic), and diazoxide (an antihypertensive that acts via opening of channels).

---