566939-85-3 Usage
Description
6-[(7S)-7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-methyl-2-naphthalenecarboxamide, also known as Orteronel, is a pharmaceutical compound with a complex chemical structure. It is an androgen synthesis inhibitor that selectively targets the enzyme CYP17A1, which is expressed in various tumor tissues such as testicular, adrenal, and prostatic tumors. This selective inhibition makes it a promising candidate for cancer treatment.
Uses
Used in Anticancer Applications:
Orteronel is used as an androgen synthesis inhibitor for the treatment of various cancers, particularly those that are androgen-dependent. By selectively inhibiting the enzyme CYP17A1, Orteronel disrupts the androgen synthesis pathway, which is crucial for the growth and survival of certain cancer cells. This inhibition can lead to a reduction in tumor growth and progression, making it a valuable tool in the fight against cancer.
Used in Drug Delivery Systems:
In the pharmaceutical industry, Orteronel is used as a key component in the development of drug delivery systems. These systems aim to improve the bioavailability, delivery, and therapeutic outcomes of the compound. By employing various carriers such as organic and metallic nanoparticles, the drug delivery systems can enhance the efficacy of Orteronel, particularly in cases where conventional treatments may be less effective.
Biological Activity
orteronel is an androgen biosynthesis inhibitor. it selectively inhibits the enzyme cyp17a1 which is expressed in testicular, adrenal, and prostatic tumor tissues. cyp17 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by its 17α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (dhea) and androstenedione, respectively, by its 17,20-lyase activity ).
in vitro
orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the ic50 value of orteronel for cortisol was about 3-fold higher than that for dhea. moreover, in human cyp17a1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and dhea production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys [1].
in vivo
after orteronel single oral dosing, serum levels of dhea, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. in castrated monkeys treated twice daily with orteronel, suppression of dhea and testosterone persisted throughout the treatment period. these findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and crpc [1].
IC 50
orteronel inhibited monkey 17,20-lyase and 17-hydroxylase activities with ic50 values of 27 and 38 nmol/l, respectively [1].
references
[1] yamaoka m, hara t, hitaka t, kaku t, takeuchi t, takahashi j, asahi s, miki h, tasaka a, kusaka m. orteronel (tak-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. j steroid biochem mol biol. 2012;129(3-5):115-28.
Check Digit Verification of cas no
The CAS Registry Mumber 566939-85-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 5,6,6,9,3 and 9 respectively; the second part has 2 digits, 8 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 566939-85:
(8*5)+(7*6)+(6*6)+(5*9)+(4*3)+(3*9)+(2*8)+(1*5)=223
223 % 10 = 3
So 566939-85-3 is a valid CAS Registry Number.
566939-85-3Relevant articles and documents
Multistep Binding of the Non-Steroidal Inhibitors Orteronel and Seviteronel to Human Cytochrome P450 17A1 and Relevance to Inhibition of Enzyme Activity
Child, Stella A.,Guengerich, F. Peter
, p. 6513 - 6522 (2020)
Orteronel (TAK-700) is a substituted imidazole that was developed for the treatment of castration-resistant prostate cancer but was dropped in phase III clinical trials. Both enantiomers of this inhibitor of cytochrome P450 (P450) 17A1 show some selectivity in differentially blocking the 17α-hydroxylation and lyase activities of the enzyme. Although both enantiomers of this compound have sub-micromolar IC50 values and bind to the enzyme with a type II spectral change (indicative of nitrogen-iron bonding) and reported Kd values of 56 and 40 nM (R and S, respectively), the rates of binding to P450 17A1 were relatively slow. We considered the possibility that the drug is a slow, tight-binding inhibitor. Analysis of the kinetics of binding revealed rapid formation of an initial complex, presumably in the substrate binding site, followed by a slower change to the spectrum of a final iron complex. Similar kinetics were observed in the interaction of another inhibitor, the triazole (S)-seviteronel (VT-464), with P450 17A1. Kinetic tests and modeling indicate that the further change to the iron-complexed form of the orteronel- or seviteronel-P450 complex is not a prerequisite for enzyme inhibition. Accordingly, the inclusion of heme-binding heterocyclic nitrogen moieties in P450 17A1 inhibitors may not be necessary to achieve inhibition but may nevertheless augment the process.
PRODUCTION METHOD OF IMIDAZOLE DERIVATIVES
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, (2013/02/28)
The present invention provides an advantageous production method of an imidazole derivative, which is suitable for industrial production. Compound (VI) is produced by reacting compound (I) with a Grignard reagent or a magnesium reagent, and a lithium reagent, and then reacting the resulting compound with compound (V).
