Disease relevance of C13749

• However, during the postpacing period with AR-L 115 BS medication, ischemia was abolished (no angina; mean left ventricular end-diastolic pressure decreased to 13 mm Hg; hemodynamic variables returned to control levels and left ventricular pump function showed some improvement while overall regional wall motion showed tendencies to improve [1].
• Sulmazole inhibited in a dose-dependent manner pertussis toxin- and cholera toxin-catalyzed labeling of Gi and Gs, respectively, with the respective inhibition observed at 100 microM of the inotrope being 29% and 56% of control [2].
• Imidazo[4,5-b]pyridines, such as AR-L57, AR-L100 and AR-L115 (Vardax), have been of interest as inotropic agents for the management of congestive heart failure [3].
• Despite its tendency to increase heart rate, high concentrations of AR-L 115 BS should not be expected to promote arrhythmias in the Purkinje system since the electrophysiological effects tend to counteract each other [4].
• In contrast to cardiac glycosides, the new compounds (amrinone, sulmazole, and derivatives) could be experimented in an attempt to antagonize the toxicity of anthracyclic compounds [5].

High impact information on C13749

• Sulmazole and pimobendane have been shown to have an additional effect on the contractile properties in that they increase the sensitivity of the myofibrils to Ca++ [6].
• Calcium-induced contraction of skinned fibers from vertebrate smooth muscle that lacks troponin is not activated by sulmazole and pimobendane [7].
• The effect on skinned fibers is due to an increase in the sensitivity of the myofilaments to calcium and, at least in the case of sulmazole, may be attributed to an increase in calcium affinity of troponin [7].
• New agents discussed are prenalterol, beta 2- and alpha-adrenergic drugs, amrinone and sulmazole [8].
• Effects of AR-L 115 BS (Sulmazol), a new cardiotonic agent, in coronary artery disease: improved ventricular wall motion, increased pump function and abolition of pacing-induced ischemia [1].

Chemical compound and disease context of C13749

• This mechanism appears to involve Gi, the inhibitory guanine nucleotide-regulatory protein, in that sulmazole attenuates the capacity of GTP to inhibit adenylate cyclase activity, and covalent modification of Gi by pertussis toxin treatment abolishes the capacity of sulmazole to mediate stimulation [9].
• In this study we have compared the effects of milrinone and sulmazole with these of AR-L100 on isolated hearts of normal rats and of rats with an experimentally induced myocardial infarction [10].
• The hemodynamic effect of 2-[(2-methoxy-4-methylsulfinyl)phenyl]- 1H-imidazo[4,5-b]pyridine (AR-L 115 BS), a new positive-inotropic substance, was studied in 10 Patients with chronic congestive heart failure after i.v. infusion of increasing does of 1.8 mg/min, 2.7 mg/min and 3.6 mg/min over a period of 40 min each [11].

Biological context of C13749

• Compound 3 was more potent and more active than the structurally related Ca(2+) sensitizers sulmazole and caffeine, but unlike them it did not increase the heart rate [12].
• In these species, however, there was no significant difference between the dose of sulmazole required to lower blood pressure by 30% from basal and that required to raise ventricular dP/dt by 50% [13].
• Both compounds are cyclic nucleotide phosphodiesterase inhibitors with similar potencies and selectivities for the Type III enzyme (IC50 BW A746C = 3.0 +/- 0.5 X 10(-5) M, sulmazole 5.0 +/- 1.9 X 10(-5) M) [13].
• Pharmacokinetics of sulmazole and II at 0.7-mg/kg iv doses were characterized by a first-order two-compartment body model [14].
• Fluoride-induced inhibition was counteracted by the G protein blocker sulmazole (1 mM), forskolin and alteration of calcium influx by increasing [Ca2+]out from 2.2 to 6 mM, raising the rate of stimulation (10 Hz, 30 s), or broadening the presynaptic action potential with 10 microM 4-aminopyridine and 50 microM tetraethylammonium chloride [15].

Anatomical context of C13749

• The effect of the new cardiotonic agent sulmazole on the guanine nucleotide regulatory protein-adenylate cyclase system was studied in rat adipocyte membranes [2].
• Activation of the sheep cardiac sarcoplasmic reticulum Ca(2+)-release channel by analogues of sulmazole [16].
• The release of calcium from the SR following the activation of the calcium-release channel by sulmazole may contribute to the positive inotropic action of this drug on mammalian cardiac muscle [17].
• Sulmazole (2-[(2-methoxy-4-methylsulfinyl)phenyl]-3H-imidazo [4,5-b] pyridine; AR-L 115 BS) and two metabolites (sulfide, sulfone) were quantified from directly injected body fluids (plasma, urine, bile) after high-performance liquid chromatographic separation [18].
• In the guinea-pig superior cervical ganglion, the Gi blocking agent sulmazole enhanced the basal and prostaglandin E2-induced stimulation of cyclic AMP synthesis but had no effect on the prostaglandin-dependent inhibition of acetylcholine release [19].

Associations of C13749 with other chemical compounds

• Several derivatives, especially 29, 9b, and 27 with a pyridyl ring in the 5-position, were ca. 2-10 times more potent on left guinea pig atria than sulmazole (ARL-115) and milrinone used as references [20].
• We then compared the effects of the novel inotropic agents MCI-154, pimobendan and sulmazole, which have direct action on cardiac myofilaments, on the acidic pH-induced changes in responses of the contractile system to Ca++ [21].
• Perhexiline was 10-fold more potent and 3-fold more efficacious than either Vardax or APP-201-533 in canine cardiac myofibrils [22].
• Furthermore, sulmazole, pimobendan and adibendan did not enhance the interaction of actin and myosin, suggesting that the mechanism of actions of these drugs are qualitatively different from that of MCI-154 [23].
• The pyridine nitrogen position in sulmazole was crucial for affinity to Na,K-ATPase (IC50 = 350 microM) because the imidazo(4,5-c)pyridines had little effect [24].

Gene context of C13749

• A special example of increase in the molecular activity towards 7-ethoxycoumarin-0-deethylation is given by the action of sulmazole on mouse liver cytochrome P-450 [25].
• In bovine facial arteries AR-L 115 BS (greater than 10(-4) mol/l) produced either no change or a small increase in tension [26].
• The effect of AR-L 115 BS on left ventricular function in patients with coronary heart disease and dilated cardiomyopathy [27].
• In anaesthetized cats dp/dtmax was augmented by maximally 141-216% at 0.1-10 mg/kg i.v. Heart rate rose after AR-L 57 BS and AR-L 115 BS by 17-38% and decreased after AR-L 100 BS by 17% [28].

Analytical, diagnostic and therapeutic context of C13749

• Sulmazole pharmacokinetics were monitored in plasma and urine by a specific, sensitive reverse-phase fully automated HPLC system with fluorimetric detection [14].
• The new cardiotonic agent AR-L 115 BS was investigated by means of the double-micro-electrode voltage clamp technique on sheep cardiac Purkinje fibres [4].
• The investigation confirmed the positive inotropic effect of AR-L 115 BS following oral administration: this substance could, therefore, be of value in the treatment of cardiac insufficiency [29].
• In a double blind crossover study in 20 healthy volunteers, aged between 19 and 32 years, 2-[(2-methoxy-4-methyl-sulfinyl)phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS) 100 mg q.i.d. for 1 week was compared with placebo [30].
• The effects of 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS) on hemodynamics, myocardial oxygen consumption and cardiac pumping efficiency were tested on closed-chest dogs in cardiac catheterization technique [31].

References