Ketodarolutamide

Ketodarolutamide (developmental code names ORM-15341, BAY-1896953) is a nonsteroidal antiandrogen (NSAA) and the major active metabolite of darolutamide (ODM-201, BAY-1841788), an NSAA which is used in the treatment of prostate cancer in men.[2][3][4][5] Similarly to its parent compound, darolutamide acts as a highly selective, high-affinity, competitive silent antagonist of the androgen receptor (AR).[2][3][4][5] Both agents show much higher affinity and more potent inhibition of the AR relative to the other NSAAs enzalutamide and apalutamide, although they also possess much shorter and comparatively less favorable elimination half-lives.[2][3][4][5] They have also been found not to activate certain mutant AR variants that enzalutamide and apalutamide do activate.[2][3][4][5] Both darolutamide and ketodarolutamide show limited central nervous system distribution, indicating peripheral selectivity, and little or no inhibition or induction of cytochrome P450 enzymes such as CYP3A4, unlike enzalutamide and apalutamide.[2][3][4][5]

Ketodarolutamide
Clinical data
Other namesORM-15341; BAY-1896953
Drug classNonsteroidal antiandrogen
Pharmacokinetic data
Elimination half-life10.0 hours[1]
Identifiers
IUPAC name
  • 3-acetyl-N-[(2S)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-1H-pyrazole-5-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
ECHA InfoCard100.235.511
Chemical and physical data
FormulaC19H17ClN6O2
Molar mass396.84 g·mol−1
3D model (JSmol)
SMILES
  • C[C@@H](CN1C=CC(=N1)C2=CC(=C(C=C2)C#N)Cl)NC(=O)C3=CC(=NN3)C(=O)C
InChI
  • InChI=1S/C19H17ClN6O2/c1-11(22-19(28)18-8-17(12(2)27)23-24-18)10-26-6-5-16(25-26)13-3-4-14(9-21)15(20)7-13/h3-8,11H,10H2,1-2H3,(H,22,28)(H,23,24)/t11-/m0/s1
  • Key:GMBPVBVTPBWIKC-NSHDSACASA-N

References
  1. Fizazi K, Massard C, Bono P, Jones R, Kataja V, James N, Garcia JA, Protheroe A, Tammela TL, Elliott T, Mattila L, Aspegren J, Vuorela A, Langmuir P, Mustonen M (2014). "Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial" (PDF). Lancet Oncol. 15 (9): 975–85. doi:10.1016/S1470-2045(14)70240-2. PMID 24974051.
  2. Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Sci Rep. 5: 12007. Bibcode:2015NatSR...512007M. doi:10.1038/srep12007. PMC 4490394. PMID 26137992.
  3. Fizazi K, Albiges L, Loriot Y, Massard C (2015). "ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer". Expert Rev Anticancer Ther. 15 (9): 1007–17. doi:10.1586/14737140.2015.1081566. PMC 4673554. PMID 26313416.
  4. Shore ND (2017). "Darolutamide (ODM-201) for the treatment of prostate cancer". Expert Opin Pharmacother. 18 (9): 945–952. doi:10.1080/14656566.2017.1329820. PMID 28490267. S2CID 20624649.
  5. Comprehensive Medicinal Chemistry III. Elsevier Science. 3 June 2017. pp. 4–. ISBN 978-0-12-803201-5.



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