Chemistry:Seviteronel
 | |
| Clinical data | |
|---|---|
| Other names | VT-464; INO-464 |
| Routes of administration | By mouth |
| Drug class | Androgen biosynthesis inhibitor; Nonsteroidal antiandrogen |
| ATC code |
|
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| Chemical and physical data | |
| Formula | C18H17F4N3O3 |
| Molar mass | 399.346 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
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 (IC50 = 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 INN.[10]
See also
References
- ↑ 1.0 1.1 1.2 1.3 1.4 "Seviteronel - Innocrin Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800035241.
- ↑ "FDA grants fast-track status for Innocrin's seviteronel to treat metastatic CRPC". PharmaceuticalTechnology. 6 January 2016. http://www.pharmaceutical-technology.com/news/newsfda-grants-fast-track-status-innocrins-seviteronel-treat-metastatic-crpc-4770025.
- ↑ "Recent progress in pharmaceutical therapies for castration-resistant prostate cancer". International Journal of Molecular Sciences 14 (7): 13958–13978. July 2013. doi:10.3390/ijms140713958. PMID 23880851.
- ↑ "Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer". Asian Journal of Andrology 16 (3): 387–400. 2014. doi:10.4103/1008-682X.129133. PMID 24759590.
- ↑ "Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors". Bioorganic & Medicinal Chemistry Letters 24 (11): 2444–2447. June 2014. doi:10.1016/j.bmcl.2014.04.024. PMID 24775307. https://zenodo.org/record/896321.
- ↑ 6.0 6.1 6.2 "Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer". Molecular Cancer Therapeutics 14 (1): 59–69. January 2015. doi:10.1158/1535-7163.MCT-14-0521. PMID 25351916.
- ↑ 7.0 7.1 "The Renaissance of CYP17 Inhibitors for the Treatment of Prostate Cancer". Cancer Drug Design and Discovery. Academic Press. 30 September 2013. pp. 341–342. ISBN 978-0-12-397228-6. https://books.google.com/books?id=HS6IAAAAQBAJ&pg=PA342.
- ↑ "Metastatic Castrate-Resistant Prostate Inhibitors: Role of Androgen Signaling Inhibitors". Prostate Cancer: A Multidisciplinary Approach to Diagnosis and Management. Demos Medical Publishing. 17 December 2014. pp. 342–. ISBN 978-1-936287-59-8. https://books.google.com/books?id=UzTtBQAAQBAJ&pg=PA342.
- ↑ "The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature". The Journal of Steroid Biochemistry and Molecular Biology 163: 136–146. October 2016. doi:10.1016/j.jsbmb.2016.04.021. 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)". WHO Drug Information (World Health Organization) 30 (3): 533. 2016. https://www.who.int/medicines/publications/druginformation/innlists/RL76.pdf.
Further reading
- "CYP17A1 inhibitors in castration-resistant prostate cancer". Steroids 95: 80–87. March 2015. doi:10.1016/j.steroids.2014.12.021. PMID 25560485.
- "Novel and next-generation androgen receptor-directed therapies for prostate cancer: Beyond abiraterone and enzalutamide". Urologic Oncology 34 (8): 348–355. August 2016. doi:10.1016/j.urolonc.2015.05.025. PMID 26162486.
External links
{{Navbox
| name = Androgens and antiandrogens | title = Androgens and antiandrogens | state = collapsed | listclass = hlist | groupstyle = text-align:center;
| group1 = Androgens
(incl. AAS)
| list1 =
| group2 = Antiandrogens | list2 = {{Navbox|child | groupstyle = text-align:center; | groupwidth = 9em;
| group1 = AR antagonists | list1 =
- Steroidal: Abiraterone acetate
- Canrenone
- Chlormadinone acetate
- Cyproterone acetate
- Delmadinone acetate
- Dienogest
- Drospirenone
- Medrogestone
- Megestrol acetate
- Nomegestrol acetate
- Osaterone acetate
- Oxendolone
- Potassium canrenoate
- Spironolactone
- Nonsteroidal: Apalutamide
- Bicalutamide
- Cimetidine
- Darolutamide
- Enzalutamide
- Flutamide
- Ketoconazole
- Nilutamide
- Seviteronel†
- Topilutamide (fluridil)
| group2 = Steroidogenesis| list2 =
inhibitors
| 5α-Reductase | |
|---|---|
| Others |
| group3 = Antigonadotropins | list3 =
- D2 receptor antagonists (prolactin releasers) (e.g., domperidone, metoclopramide, risperidone, haloperidol, chlorpromazine, sulpiride)
- Estrogens (e.g., bifluranol, [[diethylstilbestrol, estradiol, estradiol esters, ethinylestradiol, ethinylestradiol sulfonate, paroxypropione)
- GnRH agonists (e.g., leuprorelin)
- GnRH antagonists (e.g., cetrorelix)
- Progestogens (incl., chlormadinone acetate, [[cyproterone acetate, hydroxyprogesterone caproate, gestonorone caproate, [[Chemistry:Medroxyprogesterone medroxyprogesterone acetate, Chemistry:Megestrol acetate|megestrol acetate]])
| group4 = Others | list4 =
- Androstenedione immunogens: Androvax (androstenedione albumin)
- Ovandrotone albumin (Fecundin)
}}
| liststyle = background:#DDDDFF;| list3 =
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
- See also
- Androgen receptor modulators
- Estrogens and antiestrogens
- Progestogens and antiprogestogens
- List of androgens/anabolic steroids
}}
 |  |
