Seviteronel

Seviteronel
Clinical data
Other names	VT-464; INO-464
Routes of; administration	By mouth
Drug class	Androgen biosynthesis inhibitor; Nonsteroidal antiandrogen
ATC code	None;
Identifiers
	IUPAC name (1S)-1-[6,7-Bis(difluoromethoxy)naphthalen-2-yl]-2-methyl-1-(2H-triazol-4-yl)propan-1-ol;
CAS Number	1610537-15-9;
PubChem CID	78357816;
ChemSpider	32738723;
UNII	8S5OIN36X4;
CompTox Dashboard (EPA)	DTXSID401025651 ;
Chemical and physical data
Formula	C18H17F4N3O3
Molar mass	399.346 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC(C)C(C1=CC2=CC(=C(C=C2C=C1)OC(F)F)OC(F)F)(C3=NNN=C3)O;
	InChI InChI=1S/C18H17F4N3O3/c1-9(2)18(26,15-8-23-25-24-15)12-4-3-10-6-13(27-16(19)20)14(28-17(21)22)7-11(10)5-12/h3-9,16-17,26H,1-2H3,(H,23,24,25)/t18-/m0/s1; Key:ZBRAJOQFSNYJMF-SFHVURJKSA-N;

Seviteronel (developmental codes VT-464 and, formerly, INO-464) is an experimental cancer medication which is under development by Viamet Pharmaceuticals and Innocrin Pharmaceuticals for the treatment of prostate cancer and breast cancer.^[1] It is a nonsteroidal CYP17A1 inhibitor and works by inhibiting the production of androgens and estrogens in the body.^[1] As of July 2017, seviteronel is in phase II clinical trials for both prostate cancer and breast cancer.^[1] In January 2016, it was designated fast-track status by the United States Food and Drug Administration for prostate cancer.^[1]^[2] In April 2017, seviteronel received fast-track designation for breast cancer as well.^[1]

Pharmacology

Pharmacodynamics

Seviteronel is a nonsteroidal antiandrogen, acting specifically as an androgen synthesis inhibitor via inhibition of the enzyme CYP17A1, for the treatment of castration-resistant prostate cancer.^[3]^[4]^[5]^[6]^[7]^[8] It has approximately 10-fold selectivity for the inhibition of 17,20-lyase (IC₅₀Tooltip half-maximal inhibitory concentration = 69 nM) over 17α-hydroxylase (IC₅₀ = 670 nM), which results in less interference with corticosteroid production relative to the approved CYP17A1 inhibitor abiraterone acetate (which must be administered in combination with prednisone to avoid glucocorticoid deficiency and mineralocorticoid excess due to 17α-hydroxylase inhibition) and hence may be administerable without a concomitant exogenous glucocorticoid.^[9] Seviteronel is 58-fold more selective for inhibition of 17,20-lyase than abiraterone (the active metabolite of abiraterone acetate), which has IC₅₀ values for inhibition of 17,20-lyase and 17α-hydroxylase of 15 nM and 2.5 nM, respectively.^[7] In addition, in in vitro models, seviteronel appears to possess greater efficacy as an antiandrogen relative to abiraterone.^[6] Similarly to abiraterone acetate, seviteronel has also been found to act to some extent as an antagonist of the androgen receptor.^[6]

Society and culture

Generic names

Seviteronel is the generic name of the drug and its INNTooltip International Nonproprietary Name.^[10]

References

^ ^a ^b ^c ^d ^e "Seviteronel - Innocrin Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG. Archived from the original on 2015-07-22. Retrieved 2015-07-20.
^ "FDA grants fast-track status for Innocrin's seviteronel to treat metastatic CRPC". PharmaceuticalTechnology. 6 January 2016. Archived from the original on 3 June 2016. Retrieved 2 May 2016.
^ Yin L, Hu Q, Hartmann RW (July 2013). "Recent progress in pharmaceutical therapies for castration-resistant prostate cancer". International Journal of Molecular Sciences. 14 (7): 13958–13978. doi:10.3390/ijms140713958. PMC 3742227. PMID 23880851.
^ Stein MN, Patel N, Bershadskiy A, Sokoloff A, Singer EA (2014). "Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer". Asian Journal of Andrology. 16 (3): 387–400. doi:10.4103/1008-682X.129133. PMC 4023364. PMID 24759590.
^ Rafferty SW, Eisner JR, Moore WR, Schotzinger RJ, Hoekstra WJ (June 2014). "Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors". Bioorganic & Medicinal Chemistry Letters. 24 (11): 2444–2447. doi:10.1016/j.bmcl.2014.04.024. PMID 24775307.
^ ^a ^b ^c Toren PJ, Kim S, Pham S, Mangalji A, Adomat H, Guns ES, et al. (January 2015). "Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer". Molecular Cancer Therapeutics. 14 (1): 59–69. doi:10.1158/1535-7163.MCT-14-0521. PMID 25351916.
^ ^a ^b Hu Q, Hartmann RW (30 September 2013). "The Renaissance of CYP17 Inhibitors for the Treatment of Prostate Cancer". In Neidle S (ed.). Cancer Drug Design and Discovery. Academic Press. pp. 341–342. ISBN 978-0-12-397228-6.
^ Poole A, Alva A, Batten J, Agarwal N (17 December 2014). "Metastatic Castrate-Resistant Prostate Inhibitors: Role of Androgen Signaling Inhibitors". In Kelly WK, Trabulsi EJ, Zaorsky NG (eds.). Prostate Cancer: A Multidisciplinary Approach to Diagnosis and Management. Demos Medical Publishing. pp. 342–. ISBN 978-1-936287-59-8. Archived from the original on 10 January 2023. Retrieved 19 October 2016.
^ Bird IM, Abbott DH (October 2016). "The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature". The Journal of Steroid Biochemistry and Molecular Biology. 163: 136–146. doi:10.1016/j.jsbmb.2016.04.021. PMC 5046225. PMID 27154414. VT464 is another recently developed compound proposed to act as a selective lyase inhibitor, and more complete data is available in the public domain to support this claim. A review of preliminary data released suggest the IC50 for Human CYP17 lyase activity is ten times lower than for hydroxylase 15 and in nonhuman primates VT464 was able to suppress circulating testosterone as effectively as abiraterone, but with minimally depressed cortisol (remaining at 82% control compared to only 9% with aberaterone), and without associated increases in pregnenolone, progesterone and mineralocorticoids otherwise observed with abiraterone. Like Galaterone, VT464 is also in use in clinical trials without co-administration of prednisone. Together with the clear lack of suppression of circulating cortisol in nonhuman primates, these data argue that VT464 may indeed be a selective 17,20 lyase inhibitor.
^ "International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). WHO Drug Information. 30 (3). World Health Organization: 533. 2016. Archived from the original (PDF) on 2022-02-16.

External links

Seviteronel - AdisInsight

[AdisInsight-1] "Seviteronel - Innocrin Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG. Archived from the original on 2015-07-22. Retrieved 2015-07-20.

[PharmTech-2] "FDA grants fast-track status for Innocrin's seviteronel to treat metastatic CRPC". PharmaceuticalTechnology. 6 January 2016. Archived from the original on 3 June 2016. Retrieved 2 May 2016.

[pmid23880851-3] Yin L, Hu Q, Hartmann RW (July 2013). "Recent progress in pharmaceutical therapies for castration-resistant prostate cancer". International Journal of Molecular Sciences. 14 (7): 13958–13978. doi:10.3390/ijms140713958. PMC 3742227. PMID 23880851.

[pmid24759590-4] Stein MN, Patel N, Bershadskiy A, Sokoloff A, Singer EA (2014). "Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer". Asian Journal of Andrology. 16 (3): 387–400. doi:10.4103/1008-682X.129133. PMC 4023364. PMID 24759590.

[pmid24775307-5] Rafferty SW, Eisner JR, Moore WR, Schotzinger RJ, Hoekstra WJ (June 2014). "Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors". Bioorganic & Medicinal Chemistry Letters. 24 (11): 2444–2447. doi:10.1016/j.bmcl.2014.04.024. PMID 24775307.

[pmid25351916-6] Toren PJ, Kim S, Pham S, Mangalji A, Adomat H, Guns ES, et al. (January 2015). "Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer". Molecular Cancer Therapeutics. 14 (1): 59–69. doi:10.1158/1535-7163.MCT-14-0521. PMID 25351916.

[Neidle2013-7] Hu Q, Hartmann RW (30 September 2013). "The Renaissance of CYP17 Inhibitors for the Treatment of Prostate Cancer". In Neidle S (ed.). Cancer Drug Design and Discovery. Academic Press. pp. 341–342. ISBN 978-0-12-397228-6.

[KellyMD2014-8] Poole A, Alva A, Batten J, Agarwal N (17 December 2014). "Metastatic Castrate-Resistant Prostate Inhibitors: Role of Androgen Signaling Inhibitors". In Kelly WK, Trabulsi EJ, Zaorsky NG (eds.). Prostate Cancer: A Multidisciplinary Approach to Diagnosis and Management. Demos Medical Publishing. pp. 342–. ISBN 978-1-936287-59-8. Archived from the original on 10 January 2023. Retrieved 19 October 2016.

[pmid27154414-9] Bird IM, Abbott DH (October 2016). "The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature". The Journal of Steroid Biochemistry and Molecular Biology. 163: 136–146. doi:10.1016/j.jsbmb.2016.04.021. PMC 5046225. PMID 27154414. VT464 is another recently developed compound proposed to act as a selective lyase inhibitor, and more complete data is available in the public domain to support this claim. A review of preliminary data released suggest the IC50 for Human CYP17 lyase activity is ten times lower than for hydroxylase 15 and in nonhuman primates VT464 was able to suppress circulating testosterone as effectively as abiraterone, but with minimally depressed cortisol (remaining at 82% control compared to only 9% with aberaterone), and without associated increases in pregnenolone, progesterone and mineralocorticoids otherwise observed with abiraterone. Like Galaterone, VT464 is also in use in clinical trials without co-administration of prednisone. Together with the clear lack of suppression of circulating cortisol in nonhuman primates, these data argue that VT464 may indeed be a selective 17,20 lyase inhibitor.

[WHO2016-10] "International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). WHO Drug Information. 30 (3). World Health Organization: 533. 2016. Archived from the original (PDF) on 2022-02-16.

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