Novel analogues of Istaroxime, a potent inhibitor of Na(+),K(+)-ATPase: Synthesis, structure-activity relationship and 3D-quantitative structure-activity relationship of derivatives at position 6 on the androstane scaffold.

We report the synthesis and biological properties of novel analogues of Istaroxime acting as positive inotropic compounds through the inhibition of the Na(+),K(+)-ATPase. We explored the chemical space around the position 6 of the steroidal scaffold by changing the functional groups at that position and maintaining a basic oximic chain in position 3. Some compounds showed inhibitory potencies of the Na(+),K(+)-ATPase higher than Istaroxime and many of the compounds tested in vivo were safer than digoxin, the classic digitalis compound currently used for the treatment of congestive heart failure as inotropic agent. The 3D-QSAR analyses using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to a set of 63 androstane derivatives as Na(+),K(+)-ATPase inhibitors. The contour plots provide many useful insights into relationships between structural features and inhibitory potency.

Accuracy of Delivery and Effects on Absolute Humidity of Low Tidal Volume by ICU Ventilators.

BACKGROUND: During extracorporeal membrane oxygenation for ARDS, a range of 1-4 mL/kg predicted body weight tidal volume (VT) is commonly used. We explored whether such a low VT could be adequately delivered by ICU ventilators, and whether such low VTs prevent the heated humidifier (HH) from reaching the recommended target of 33 mg/L absolute humidity (AH). METHODS: We attached a lung model to 5 ICU ventilators set in volume controlled mode and body temperature and pressure saturated. We ran 2 protocols over a 100-280 mL VT range used with adult or neonatal breathing circuit at a breathing frequency (f) of 15 (f15) or 30 (f30) breaths/min. In the first protocol, with the HH off, VT was measured with a dedicated data logger and expressed in body temperature and pressure saturated. The relationships of measured VT to set VT were studied, and the relative error in VT was analyzed within its 10% boundaries. In the second protocol, the HH was on, and we measured AH using a psychrometric method. The relationship of AH to set VT was analyzed with linear regression. RESULTS: For the 5 ventilators used, the slope (95% CI) between measured VT versus set VT averaged 0.93 (0.92-0.93), 0.93 (0.93-0.94), 0.91 (0.90-0.91), and 0.91 (0.90-0.91) mL/mL for adult and neonatal circuits at f15 and f30, respectively (P < .05 vs 1 in each instance), indicating a systematic under-delivery of VT. The VT relative error fell within the ±10% accuracy range for only 2 ventilators with adult circuits at f15 and f30. AH increased linearly with VT. The recommended target of 33 mg/L AH was reached with all of the ventilators for the adult circuit at f30 only. The minimum volume that met the recommended threshold for AH was 100, 150, 190, 160, and 100 mL for the G5, Carestation, PB980, Servo-U, and V500 ventilators, respectively, at f30. CONCLUSION: Low VT was systematically under-delivered by modern ICU ventilators by roughly 7-9%. To meet the recommended target of 33 mg/L AH, adult circuit at f30 should be used.

Istaroxime, a stimulator of sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a activity, as a novel therapeutic approach to heart failure.

Interventions involving calcium cycling may represent a promising approach to heart failure (HF) therapy because calcium handling is known to be deranged in human and experimental HF. Istaroxime is a sodium-potassium adenosine triphosphatase (ATPase) inhibitor with the unique property of increasing sarcoplasmic reticulum calcium ATPase (SERCA) isoform 2a (SERCA2a) activity. Because this was demonstrated in normal experimental models, we investigated whether istaroxime is able to improve global cardiac function and stimulate SERCA in failing hearts. In guinea pigs with 3-month aortic banding (AoB), echocardiographic results showed that istaroxime intravenous infusion (0.11 mg/kg per min) significantly increased both indices of contraction and relaxation (fractional shortening, +18+/-3.7%; aortic flow rate, +19+/-2.9%; peak myocardial systolic velocity, +36+/-7%; circumferential fiber shortening, +24+/-4.1%; peak atrial flow velocity, +69+/-8.6%; isovolumic relaxation time, +19+/-6.9%; and peak myocardial early diastolic velocity, +42+/-12%). In left ventricular sarcoplasmic reticulum microsomes from AoB animals, 100 nmol/L istaroxime normalized the depressed (-32%) SERCA2a maximum velocity and increased SERCA activity (+17%). In muscle strips from hearts from patients undergoing cardiac transplantation, istaroxime (0.1-1.0 micromol/L) increased (in a concentration-dependent manner) developed tension, the maximum and minimum first derivative of tension, and absolute velocity of contraction, while stimulating SERCA activity in sarcoplasmic reticulum microsomes at physiologic free calcium concentrations. In conclusion, istaroxime is presently the only available compound that stimulates SERCA2a activity and produces a luso-inotropic effect in HF.

Novel analogues of istaroxime, a potent inhibitor of Na+,K+-ATPase: synthesis and structure-activity relationship.

We report the synthesis and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as positive inotropic compounds. Following our previously described model from which Istaroxime was generated, the 5alpha,14alpha-androstane skeleton was used as a scaffold to study the space around the basic chain of our lead compound. Some compounds demonstrated higher potencies than Istaroxime on the receptor and the (E)-3-[(R)-3-pyrrolidinyl]oxime derivative, 15, was the most potent; as further confirmation of our model, the E isomers of the oxime are more potent than the Z form. The compounds tested in the guinea pig model induced positive inotropic effects, which are correlated to the in vitro inhibitory potency on the Na(+),K(+)-ATPase. The finding that all tested compounds resulted less proarrhythmogenic than digoxin, a currently clinically used positive inotropic agent, suggests that this could be a feature of the 3-aminoalkyloxime derivative class of 5alpha,14alpha-androstane.