Rogletimide
Clinical data
Other namesRoglethimide; Pyridoglutethimide
Routes of
administration		By mouth
Drug classAromatase inhibitor
Identifiers
  • 3-ethyl-3-(pyridin-4-yl)piperidine-2,6-dione
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC12H14N2O2
Molar mass218.256 g·mol−1
3D model (JSmol)
  • O=C1NC(=O)CCC1(c2ccncc2)CC

Rogletimide, also known as pyridoglutethimide, is a medication which was never marketed.[1] It is related in chemical structure to the sedative/hypnotic drug glutethimide, but instead has pharmacological activity as a selective aromatase inhibitor similar to the related drug aminoglutethimide and has no significant sedative-hypnotic effect.[2] This makes it potentially useful in the treatment of breast cancer, and with fewer side effects than aminoglutethimide, but its lower potency caused it to be unsuccessful in clinical trials.[1][3]

Pharmacodynamics of aromatase inhibitors
GenerationMedicationDosage % inhibitionaClassbIC50c
FirstTestolactone250 mg 4x/day p.o. ?Type I ?
100 mg 3x/week i.m. ?
Rogletimide200 mg 2x/day p.o.
400 mg 2x/day p.o.
800 mg 2x/day p.o.		50.6%
63.5%
73.8%		Type II ?
Aminoglutethimide250 mg mg 4x/day p.o.90.6%Type II4,500 nM
SecondFormestane125 mg 1x/day p.o.
125 mg 2x/day p.o.
250 mg 1x/day p.o.		72.3%
70.0%
57.3%		Type I30 nM
250 mg 1x/2 weeks i.m.
500 mg 1x/2 weeks i.m.
500 mg 1x/1 week i.m.		84.8%
91.9%
92.5%
Fadrozole1 mg 1x/day p.o.
2 mg 2x/day p.o.		82.4%
92.6%		Type II ?
ThirdExemestane25 mg 1x/day p.o.97.9%Type I15 nM
Anastrozole1 mg 1x/day p.o.
10 mg 1x/day p.o.		96.7–97.3%
98.1%		Type II10 nM
Letrozole0.5 mg 1x/day p.o.
2.5 mg 1x/day p.o.		98.4%
98.9%–>99.1%		Type II2.5 nM
Footnotes: a = In postmenopausal women. b = Type I: Steroidal, irreversible (substrate-binding site). Type II: Nonsteroidal, reversible (binding to and interference with the cytochrome P450 heme moiety). c = In breast cancer homogenates. Sources: See template.

Synthesis

Synthesis:[4] Patent:[5]

Base catalyzed alkylation of ethyl 4-pyridylacetate [54401-85-3] (1) with iodoethane gives ethyl 2-(4-pyridyl)butyrate [76766-56-8] (2). Base catalyzed conjugate addition of the carbanion to acrylamide (3) gives (4). The last step is an intramolecular cyclization to rogletimide (5).

References

  1. 1 2 Frederick A. Luzzio (17 May 2019). Imides: Medicinal, Agricultural, Synthetic Applications and Natural Products Chemistry. Elsevier Science. pp. 361–. ISBN 978-0-12-815676-6.
  2. ↑ Vanden Bossche HV, Moereels H, Koymans LM (1994). "Aromatase inhibitors--mechanisms for non-steroidal inhibitors". Breast Cancer Research and Treatment. 30 (1): 43–55. doi:10.1007/bf00682740. PMID 7949204. S2CID 24414161.
  3. ↑ MacNeill FA, Jones AL, Jacobs S, Lønning PE, Powles TJ, Dowsett M (October 1992). "The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer". British Journal of Cancer. 66 (4): 692–7. doi:10.1038/bjc.1992.339. PMC 1977412. PMID 1419608.
  4. ↑ Boss, Aileen M.; W. Clissold, Derek; Mann, John; Markson, Andrew J.; Thickitt, Christopher P. (1989). "A concise synthesis of racemic pyridoglutethimide and its resolution using chiral stationary phase HPLC". Tetrahedron. 45 (18): 6011–6016. doi:10.1016/S0040-4020(01)89128-6.
  5. ↑ Derek W. Clissold, John Mann, Christopher P. Thickitt, US5112976 (1992 to National Research Development Corporation).


This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.