203737-93-3

Usage

Biological Activity

istaroxime is a positive inotropic agent that mediates its action through inhibition of sodium/potassium adenosine triphosphatase (na+/k+ atpase). istaroxime is an investigational drug originally patented and developed by the italian pharmaceutical company sigma-tau. istaroxime is now under development for treatment of acute decompensated heart failure by cvie therapeutics.

in vitro

pst2744 inhibited the na+/k+-atpase activity from dog kidney with an ic50 value of 0.43 ± 0.15 μm [1]. the transient inward current (i(ti)) induced by a ca(2+) transient in the presence of complete na(+)/k(+) pump blockade was inhibited (-43%) by pst2744 but not by digoxin [2].

in vivo

intravenous infusion of 0.2 mg/kg/min pst2744 in anesthetized guinea pigs exerted an immediate and long-lasting inotropic effect (ed(80) of 1.89 +/- 0.37 mg/kg) without causing lethal arrhythmias up to a cumulative dose of 18 mg/kg [1]. 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%) [3]. in 5 animals, pst-2744 effects were compared with dobutamine. heart rates, pr intervals and qt intervals were unchanged following pst-2744 administration. pst-2744 increased contractility (+dp/dt) by 56% from 1881 +/- 282 mm hg/s to 2939 +/- 734 mm hg/s (p < 0.01) [4].

IC 50

0.43 ± 0.15 μm (na+/k+-atpase activity from dog kidney) [1]

Upstream product

• 500148-41-4 androstane-3,6,17-trione 
• 37866-45-8 2-aminoethoxyamine dihydrochloride 
• 304-91-6 2-iodoxybenzoic acid 
• 600178-31-2 (Z)-3-(2-aminoethoxyimino)androstane-6α,17β-diol 
• 1046809-23-7 [(E)-2-(6,17-dioxoandrostane-3-ylideneaminooxy)ethyl]carbamic acid 9H-fluoren-9-ylmethyl ester 
• 2243-06-3 androst-4-ene-3,6,17-trione 
• 53-43-0 dehydroepiandrosterone 
• 2243-05-2 5α-androst-3,6,17-trione 
• 1046809-24-8 [(Z)-2-(6,17-dioxoandrostane-3-ylideneaminooxy)ethyl]carbamic acid 9H-fluoren-9-ylmethyl ester 
• 74395-56-5 5α-hydroxyandrostane-3,6,17-trione 

Relevant academic research and scientific papers

Novel approach to the synthesis of istaroxime

Istaroxime 1, a novel cardiotonic agent with high efficiency and low toxicity was synthesized from dehydroepiandrosterone 2 using a novel approach that included epoxidation, ring-opening, substitution, and oximation. The new protocol without gas protection was milder than the reported approaches. The overall yield of the method was 24.1%.

Novel synthesis method of Istaroxime

The invention belongs to the field of pharmaceutical chemistry, and discloses a novel synthesis method of Istaroxime. The method comprises the following steps: by using dehydrogenated epiandrosterone as an initial raw material, carrying out epoxidation, ring opening, reduction, oxidation and other reactions to prepare an intermediate M-06; by using ethyl benzoate as an initial raw material, reacting the ethyl benzoate with hydroxylamine hydrochloride to obtain phenyl hydroximic acid, carrying out hydrochlorination and chlorination by using ethanolamine as a raw material to obtain dichloroacetate, and carrying out substitution, hydrolysis and other reactions on the dichloroacetate and the phenyl hydroximic acid to obtain an intermediate M-11; and finally, reacting the M-06 with the M-11 to obtain the end product Istaroxime. According to the method, in the intermediate M-06 synthesis process, the polarity of all the intermediates has great differences from that of the impurities and reaction reagents; and in the intermediate 11 synthesis process, the active spots capable of participating in the chemical reaction in the reaction substrate are simple. Therefore, the method can achieve the requirements without carrying out column chromatography purification, thereby simplifying the synthesis after-treatment process.

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 5α,14α-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 5α,14α-androstane.

Process for the preparation of (E,Z) 3-(2-aminoethoxyimino)-androstane-6,17-dione and its analogues

An improved process is described for the preparation of compounds with general formula (I) and particularly for the preparation of the compound (E,Z) 3-(2-aminoethoxyimino)-androstane-6,17-dione, in which n=1 and R1=R2=H.

6-Hydroxy and 6-oxo-androstane derivatives active on the cardiovascular system and pharmaceutical compositions containing same

6-hydroxy and 6-oxo-androstane derivatives of formula (I), active on the cardiovascular system. STR1 wherein: the symbol A represents CH--OR, C=N--OR, CH--CH=N--OR and C=CH--N--OR; and R1, R2 and R3 are as defined herein.