5N-Bicalutamide

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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]

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 the most potent AR antagonist to have been developed thus far.[1]

See also

References

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  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


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