A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure-activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(-) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.

ZENECA ZM181,037 is a novel eukalemic diuretic from a series of 1,1-diarylcarbin-1-01-2 amines. In contrast to the standard diuretic hydrochlorothiazide, the blood pressure-lowering effect was not observed with ZENECA ZM 181,037 in spontaneously hypertensive rats. ZENECA ZM 181,037 demonstrated a K⁺ channel-blocker profile. In the isolated rat aorta stimulated with 20 mmol/l KC1, both the d- and l-enantiomer of ZENECA ZM 181,037 antagonized the relaxation of cromakalim with mean pK_B values of 6.4 and 6.7, respectively. In the isolated guinea-pig portal vein and urinary detrusor muscle, both enantiomers enhanced the spontaneous myogenic activity at concentrations of 1 µmol/l and higher, in addition to antagonizing the effect of cromakalim. ZENECA ZM 181,037, similar to glibenclamide, prevented a significant increase in ⁸⁶Rb⁺ by cromakalim in both portal vein and detrusor muscle strips; however, ZENECA ZM 181,037, dissimilar to glibenclamide and tolbutamide, did not increase plasma glucose when given orally to dogs. Thus, ZENECA ZM 181,037 is a blocker of the ATP-sensitive K⁺ channel (K_ATP) in vascular and nonvascular tissues. In view of the profound saluresis produced by ZENECA ZM 181,037, the lack of antihypertensive effect appears to result from its blocking activity on K_Aχp in vascular tissues.

ABSTRACT-ICI 181,037, the most active compound from a series of 1,1-diaryl carbin-1-ol-2 amines, was evaluated for diuretic and cardiovascular activity. In saline loaded rats, the magnitude of water diuresis and saluresis produced by ICI 181,037 (10 mg/kg, p.o.) was equal to that of hydrochlorothiazide. Water diuresis and saluresis produced by ICI 181,037 were enhanced with SKF 525A, ampicillin or neomycin plus lincomycin, suggesting that ICI 181,037 is an active diuretic. In conscious dogs, the saluretic activity of ICI d-181,037 (5 mg/kg, p.o.) was about 80% of the corresponding hydrochlorothiazide value, whereas the 1-isomer demonstrated only minimum saluretic activity. In both rats and dogs, the concurrent kaliuresis after ICI 181,037 or its enan tiomers was minimal as compared to hydrochlorothiazide. Following chronic dosing with diuretic doses, the basal levels of plasma potassium in dogs were not altered. In amphibian in vitro models for mimicking mammalian nephron, ICI 181,037 and its enantiomers demonstrated antinatriferic and antichloriferic activities, suggesting multi ple renal sites of action for this agent. Racemic ICI 181,037 and its isomers reversed ouabain-induced arrhythmia in dogs and/or reduced the ouabain-induced mortality in mice after intravenous administration. It is concluded that ICI 181,037, particularly its d-isomer, is a novel eukalemic diuretic and possesses antiarrhythmic activity.Diuretics have been used as a major treat ment of renal and cardiovascular disorders for more than three decades. The relative success of diuretic therapies has been based upon their relatively low cost, easy titration, good patient tolerability, and few subjective and im mediate side effects. Electrolyte alterations and metabolic abnormalities are the primary adverse effects. There is an abundance of literature suggesting that diuretic-induced hypokalemia may lead to the occurrence of cardiac arrhythmia (1 7), although current opinions on this issue are not necessarily unanimous. Nevertheless, the available data concerning the arrhythmogenic potential of kaliuretic diuretics are substantial enough to warrant some precautions on the part of the clinician (8). It is evident that hypokalemia in duced by diuretics is a cause for concern in clinical practice. Thus, a saluretic agent which induces less urinary potassium loss resulting in eukalemia will be an attractive therapeutic agent. We report here on the pharmacology of ICI 181,037 (R * S * -2-[2-dimethylamino-l-hy droxy-1-(2-methoxy-5 (1, 1-dimethylethyl)-phen yl)propyl) phenoxy]acetamide), a eukalemic diuretic which possesses an antiarrhythmic property (Fig. 1).

ZENECA ZM224,832 is a novel eukalemic diuretic from the aminomethylphenol pyrazine series which demonstrated a profile of calcium channel blockers. It produced diuretic and saluretic effects in animals but had only minimal alterations in kaliuresis after oral administration. In contrast to standard diuretics, the plasma K⁺ concentration was not altered in conscious dogs treated for 14 days with ZENECA ZM224,832 and the concurrent plasma renin activity was also minimally elevated. The isolated rat aorta evaluation indicated that ZENECA ZM224,832, like tiapamil and nifedipine, inhibited vascular smooth muscle tone by inhibiting voltage-dependent calcium channels. ZENECA ZM224,832 produced a dose-dependent decrease of blood pressure in spontaneously hypertensive rats (SHR) in which the antihypertensive activity was not noted with HCTZ. In addition, ZENECA ZM224,832, similar to diltiazem, produced an acute blood pressure lowering effect in nephrectomized SHR which was independent of its diuretic activity. It is concluded that ZENECA ZM224,832 is a potent eukalemic diuretic with calcium channel blocking properties.

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