Second-Generation Androgen Receptor Antagonists as Hormonal Therapeutics for Three Forms of Prostate Cancer

Abstract

Enzalutamide is the first second-generation nonsteroidal androgen receptor (AR) antagonist with a strong binding affinity to AR. Most significantly, enzalutamide can prolong not only overall survival time and metastatic free survival time for patients with lethal castration-resistant prostate cancer (CRPC), but also castration-resistant free survival time for patients with castration-sensitive prostate cancer (CSPC). Enzalutamide has thus been approved by the US Food and Drug Administration (FDA) for the treatment of both metastatic (in 2012) and non-metastatic (in 2018) CRPC, as well as CSPC (2019). This is an inspiring drug discovery story created by an amazing interdisciplinary collaboration. Equally important, the successful clinical use of enzalutamide proves the notion that the second-generation AR antagonists can serve as hormonal therapeutics for three forms of advanced prostate cancer. This has been further verified by the recent FDA approval of the other two second-generation AR antagonists, apalutamide and darolutamide, for the treatment of prostate cancer. This review focuses on the rational design and discovery of these three second-generation AR antagonists, and then highlights their syntheses, clinical studies, and use. Strategies to overcome the resistance to the second-generation AR antagonists are also reviewed.

Keywords: androgen receptor; apalutamide; darolutamide; enzalutamide; prostate cancer.

Figure 1

Timeline for the development of hormonal therapeutics for prostate cancer.

Figure 2

First generation of nonsteroidal AR antagonists.

Figure 3

Second generation of nonsteroidal AR antagonists.

Figure 4

Discovery of enzalutamide and apalutamide.

Scheme 1

Overview of synthetic approaches to hydantoin-based enzalutamide and apalutamide.

Scheme 2

Synthesis of isothiocyanate fragments of enzalutamide and apalutamide. Reaction conditions: (a) CSCl₂, H₂O; (b) AcOH, H₂O, reflux; (c) HNO₃, H₂SO₄, 90 °C; (d) POCl₃, PCl₅, 110–120 °C; H₂, (e) Raney Ni, THF; (f) Boc₂O, pyridine, DMAP, rt; (g) KCN, CuCN, phenantroline, DMA, 110 °C; (h) TFA, CH₂Cl₂; (i) POBr₃, PBr₃, Br₂, 90–110 °C; (j) CuCN, phenantroline, CH₃CONMe₂, 160 °C; (k) AcOH, Fe.

Scheme 3

Nitration-free synthesis of the substituted pyridine intermediate 17. Reaction conditions: (a) NIS, DMF, CH₃CN, 80 °C; (b) POCl₃, DMF, microwave 130 °C; (c) PMBNH₂, Pd(OAc)₂, BINAP, Et₃N, CsCO₃, toluene; (d) Zn(CN)₂, Pd₂(dba)₃, dppf, DMF, 110 °C; (e) TFA, CH₂Cl₂.

Scheme 4

Synthesis of the amino nitrile 26 (top) and amino ester 29 (bottom) for the assembly of enzalutamide. Reaction conditions: (a) CrO₃, H₅IO₆, CH₃CN, CH₂Cl₂; (b) SOCl₂, DMF, then MeNH₂; (c) Fe, AcOH, EtOAc, reflux; (d) 2-cyano-2-hydroxypropane, MgSO₄, EtOAc, 80 °C; (e) 13, DFM, microwave 100 °C; (f) SOCl₂, DMF (cat), 2-PrOAc, 60 °C, then MeNH₂; (g) 2-aminoisobutyric acid, CuI, K₂CO₃, 2-acetylcyclohexanone, DMF, H₂O, 105 °C; (h) MeI, K₂CO₃, DMF, H₂O, 40 °C; 13, DMSO, 2-PrOAc, 83–83 °C.

Scheme 5

Two options for synthesis of amino nitrile 32 for the assembly of apalutamide. Reaction conditions: (a) MeNH₂, THF; (b) PMBNH₂, MeCN, microwave 190 °C; (c) TFA, CH₂Cl₂; (d) cyclobutanone, NaCN; (e) 18, CSCl₂, MeCONMe₂, 80 °C, then HCl, MeOH; (f) Me₂NH–HCl, CDI, Et₃N, CH₂Cl₂, rt; (g) Fe, AcOH, EtOAc, reflux; (h) cyclobutanone, TMSCN, AcOH, 80 °C.

Scheme 6

Cyclobutanecarboxylic acid-based approaches to the advanced intermediate 39 needed for assembly of apalutamide. Reaction conditions: (a) DMF, K₂CO₃, CuCl, H₂O, 100–105 °C; (b) i-Pr₂Net, Et₃N, CH₂Cl₂, reflux; (c) MeI, DMF, K₂CO₃, rt; (d) 18, DMSO, 2-PrOAc, 90 °C.

Scheme 7

Synthesis of thiohydantoin core of apalutamide and late-stage amide formation. Reaction conditions: (a) cyclobutanone, NaCN, AcOH; (b) 17, 1,1′-thiocarbonylbis(pyridine-2(1H)-one, toluene, 100 °C then HCl, EtOH, DMA, 70 °C; (c) n-C₅H₁₁MgBr, THF, CO₂, then CDI, MeNH₂, THF; or Pd(t-Bu₃P)₂, CO (5 bar), i-Pr₂Net, MeNH₂, THF, 60 °C; or Pd(OAc)₂, dppf, i-Pr₂NH, CO, MeOH, 60 °C, then MeNH₂, MeOH.

Scheme 8

Synthesis of advanced intermediate ester 49 via late-stage formation of thiohydantoin. Reaction conditions: (a) CDI, DBU, i-Pr₂NEt, THF, 55–65 °C; (b) HCl, 2-PrOH; (c) methyl 4-bromo-2-fluorobenzoate (47), acetylacetone, CuI, K₂CO₃, DMF, 120–130 °C; CSCl₂, DMAP, THF, 40–50 °C.

Scheme 9

Synthesis of apalutamide via late-stage, thiophosgene-free cyclization. Reaction conditions: (a) 12, CDI, DBU, i-Pr₂NEt, THF, 60 °C; (b) HCl, 2-PrOH, 70 °C; (c) 28, DMA, KOAc, CuBr, TMEDA, 120 °C; (d) 1,1′-thiocarbonylbis(pyridine2(1H)-one, DMAP, DMA, 90 °C.

Scheme 10

Synthesis of enzalutamide via functionalization of thiohydantoin. Reaction conditions: (a) thiourea, Et₃N, DMF, 80–90 °C; (b) 4-bromo-3-(trifluoromethyl)-benzonitrile (55), NaH, DMF, rt; (c) 28, NaH, DMF.

Scheme 11

Synthesis of apalutamide using atom-economical formation of isothiohydantoin core. Reaction conditions: (a) KSCN, i-Pr₂NEt, MeOH/H₂O, reflux; (b) 59, K₂CO₃, CuI, DMF, 100–110 °C.

Scheme 12

Synthesis of darolutamide. Reaction conditions: (a) n-BuLi, THF, toluene; (b) (i-PrO)₃B; (c) pinacol, AcOH; (d) 62, Pd(OAc)₂, K₂CO₃, CH₃CN/H₂O, 70 °C; (e) aq HCl, MeOH, 10 °C; (f) 64, PPh₃, DIAD, EtOAc; (g) aq HCl, 45 °C; (h) 66, T3P, EtOAc, i-Pr₂NEt, 10 °C; (i) NaBH₄, EtOH.

Figure 5

Mechanism of action of different hormonal therapies in AR signaling pathway. * First generation nonsteroidal AR antagonist.

Figure 6

Mechanisms of resistance to the second-generation AR antagonists.