ODM-201

ODM-201

ODM-201
Systematic (IUPAC) name
N((R)-1-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide[1]
 N   

ODM-201 (also known as BAY-1841788) is a non-steroidal antiandrogen, specifically, a full and high-affinity antagonist of the androgen receptor (AR), that is under development by Orion and Bayer HealthCare[1] for the treatment of advanced, castration-resistant prostate cancer (CRPC).[2][3]

Relative to enzalutamide (MDV3100 or Xtandi) and apalutamide (ARN-509), two other recent non-steroidal antiandrogens, ODM-201 shows some advantages.[3] ODM-201 appears to negligibly cross the blood-brain-barrier.[3] This is beneficial due to the reduced risk of seizures and other central side effects from off-target GABAA receptor inhibition that tends to occur in non-steroidal antiandrogens that are structurally similar to enzalutamide.[3] Moreover, in accordance with its lack of central penetration, ODM-201 does not seem to increase testosterone levels in mice or humans, unlike other non-steroidal antiandrogens.[3] Another advantage is that ODM-201 has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently-identified clinically-relevant F876L mutation that produces resistance to enzalutamide and ARN-509.[3] Finally, ODM-201 shows higher affinity and inhibitory efficacy at the AR (Ki = 11 nM relative to 86 nM for enzalutamide and 93 nM for ARN-509; IC50 = 26 nM relative to 219 nM for enzalutamide and 200 nM for ARN-509) and greater potency/efficaciousness in non-clinical models of prostate cancer.[3]

ODM-201 has been studied in phase I and phase II clinical trials and has thus far been found to be effective and well-tolerated,[4] with the most commonly reported side effects including fatigue, nausea, and diarrhea.[5][6] No seizures have been observed.[7][6] As of July 2015, ODM-201 is in phase III trials for CRPC.[3]

ORM-15341 is the main active metabolite of ODM-201.[3] It, similarly, is a full antagonist of the AR, with an affinity (Ki) of 8 nM and an IC50 of 38 nM.[3]

See also

References

  1. ^ .  
  2. ^ 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.  
  3. ^ a b c d e f g h i j 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.  
  4. ^ "ODM-201 is safe and active in metastatic castration-resistant prostate cancer". Cancer Discov 4 (9): OF10. 2014.  
  5. ^ Pinto Á (2014). "Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer". Cancer Biol. Ther. 15 (2): 149–55.  
  6. ^ a b 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". Lancet Oncol. 15 (9): 975–85.  
  7. ^ Agarwal N, Di Lorenzo G, Sonpavde G, Bellmunt J (2014). "New agents for prostate cancer". Ann. Oncol. 25 (9): 1700–9.  

External links

  • ODM-201 - AdisInsight