Anti-prostate cancer (PC) agents Abiraterone (abi) and galeterone (gal) are 3-OH-Δ5-C17-heterocycles substituted steroids. Their structural feature mimic endogenous precursors (dehydroepiandrosterone and pregnenolone) of the androgens {Testosterone (T) and dihydrotestosterone (DHT)} in the steroidogenesis pathway. These agents inhibit the 17-lyase enzyme (CYP17A1) which is responsible for steroid-C17 modification. Unlike abi, gal is unique due to its multi-target activities such as AR antagonism and induction of AR degradation. In the androgen axis the 3β-hydroxysteroid dehydrogenase (3β-HSD) is another important enzyme which converts 3-OH-Δ5 steroids to 3-oxo-Δ4 (T) which is further converted to potent androgen (DHT) by the action of 5α-reductase enzyme. 3β-HSD also known for metabolism of abi and gal due to their structural similarity to endogenous ligands. Consequently, both abi and gal have short half-lives in mice (1.5 h and 45 min respectively). These two agents also suffer from lower oral bioavailability (37 and ~19% in mouse, respectively), and thus, the need high therapeutic oral doses (1000 and 2550 mg/day, respectively) for the treatment of men with PC. Despite of the modest pharmacokinetics profile, abi was approved by the FDA for clinical use. Abi’s robust efficacy in the clinic may be due to the superior anti-PC activity of its first/major metabolite (3-OH-Δ4-Abi). Unfortunately, gal’s first/major metabolite (3-oxo-Δ4-gal) is not as potent as 3-OH-Δ4-Abi, which may be a reason for its failure in the phase III clinical trials. In the current study, we have synthesized various C3-analogs of gal and determined their anti-PC activities. We will be present the rationale for the design, their synthesis, in vitro SAR and in vivo anti-PC activities, pharmacokinetics, toxicity profiles of the most active compounds, VNPP414 and VNPP433-3β. Simple modification at metabolic soft spot markedly improved half-lives, oral absorption and acceptable toxicity profiles. Our results support advancing VNPP433-3β to the clinic.

Development of novel C3-analogs of galeterone for prostate cancer therapy

2019 Spring National Meeting

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