5N-Bicalutamide

5N-Bicalutamide, or 5-azabicalutamide, is a highly potent nonsteroidal antiandrogen (NSAA) which was discovered in 2016.[1][2] It is a structural modification of bicalutamide differing it from it only by the replacement of a carbon atom with a nitrogen atom in one of its phenyl rings.[1] Similarly to bicalutamide, the drug acts as a selective antagonist of the androgen receptor (AR).[1] However, unlike bicalutamide, it is a reversible covalent antagonist and stays bound to the receptor for a far longer amount of time.[1] As a result of this difference, 5N-bicalutamide has markedly improved potency relative to bicalutamide, with approximately 150-fold higher affinity for the AR (Ki = 0.15 nM versus 22.3 nM) and about 20-fold greater functional inhibition (IC50 = 15 nM versus 310 nM) of the AR.[1] Future studies of 5N-bicalutamide in normal and mutated prostate cancer cells are planned or underway and it is anticipated that N-bicalutamide may be able to overcome resistance to current antiandrogens that are used in the treatment of prostate cancer.[1]

5N-Bicalutamide
Clinical data
Other names5-Azabicalutamide
Drug classNonsteroidal antiandrogen
ATC code
  • None
Identifiers
IUPAC name
  • N-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylpropanamide
CAS Number
PubChem CID
UNII
Chemical and physical data
FormulaC17H13F4N3O4S
Molar mass431.36 g·mol−1
3D model (JSmol)
SMILES
  • CC(CS(=O)(=O)C1=CC=C(C=C1)F)(C(=O)NC2=CN=C(C(=C2)C(F)(F)F)C#N)O
InChI
  • InChI=1S/C17H13F4N3O4S/c1-16(26,9-29(27,28)12-4-2-10(18)3-5-12)15(25)24-11-6-13(17(19,20)21)14(7-22)23-8-11/h2-6,8,26H,9H2,1H3,(H,24,25)
  • Key:JWQMHMGGGRQTSY-UHFFFAOYSA-N

Enzalutamide and related second-generation NSAAs like RD-162 and apalutamide were derived from bicalutamide and as a result are similar to it in chemical structure.[1] They have up to about 10-fold higher affinity for the AR than does bicalutamide and hence are comparatively more potent and efficacious antiandrogens.[1] However, their structures are rigidified such that the analogous structural modification that was done with bicalutamide to create 5N-bicalutamide could not be used to increase affinity or potency with them.[1] Enzalutamide was described in 2013 as "the emperor of all antiandrogens" and other second-generation NSAAs have similar potency to it,[3] so 5N-bicalutamide would appear to be among the most potent AR antagonists to have been developed thus far.[1]

See also

References
  1. de Jesus Cortez F, Nguyen P, Truillet C, Tian B, Kuchenbecker KM, Evans MJ, Webb P, Jacobson MP, Fletterick RJ, England PM (2017). "Development of 5N-Bicalutamide, a High-Affinity Reversible Covalent Antiandrogen". ACS Chem. Biol. 12 (12): 2934–2939. doi:10.1021/acschembio.7b00702. PMID 28981251. S2CID 24974359.
  2. Pamela, M., Fletterick, R. J., Kuchenbecker, K., & de Jesus Cortez, F. (2016). U.S. Patent Application No. 15/382,942. https://www.google.com/patents/US20170101384
  3. Antonarakis ES (2013). "Enzalutamide: The emperor of all anti-androgens". Transl Androl Urol. 2 (2): 119–120. doi:10.3978/j.issn.2223-4683.2012.09.04. PMC 3785324. PMID 24076589.


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