Orteronel ((S)-Orteronel)(TAK-700) was selected as a candidate for clinical evaluation. orteronel (TAK-700) is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer.

17, 20-lyase (human):38 nM

In monkey adrenal cells, orteronel suppresses ACTH-induced DHEA and androstenedione production, achieving IC50 values of 110 nM and 130 nM, respectively. Additionally, it significantly reduces DHEA synthesis in the human adrenocortical tumor line H295R, with an IC50 of 37 nM[1]. Orteronel demonstrates potent inhibition of both rat and human steroid 17,20-lyase, displaying IC50 values of 54 nM and 38 nM, accordingly. Importantly, it does not markedly impact other CYP isoforms, including 11-hydroxylase and CYP3A4. However, it notably exerts a stronger inhibitory effect on 17,20-lyase activity in microsomes expressing human CYP isoforms, with an IC50 of 19 nM, distinguishing its specificity compared to other CYP isoforms[2].

Orteronel administered orally at a dosage of 1 mg/kg demonstrates effective pharmacokinetic properties, characterized by a peak concentration time (Tmax) of 1.7 hours, a maximum concentration (Cmax) of 0.147 μg/mL, a half-life (t1/2) of 3.8 hours, and an area under the curve (AUC0-24 hours) of 0.727 μg/mL[1]. Additionally, this dosage significantly lowers serum testosterone and dehydroepiandrosterone (DHEA) levels in cynomolgus monkeys[2].

Rat 11-hydroxylase activity is measured according to a method described for side-chain cleavage activity previously with some modifications. The reaction mixture contained 200 mM mannitol, 4.5 mM HEPES, 2.3 mM potassium phosphate (pH 7.4), 0.1 mM EDTA·2 K, 0.03% BSA (crystallized), 4.5 mM NADPH, 11 mM calcium chloride, 4 μg of mitochondria protein, 10 nM [1,2-3H]-hydroxy-11-deoxycorticosterone (11-deoxycortisol) (NEN, dissolved in 0.02% Tween-80), and 1-1000 nM test compounds in a total volume of 150 μL. The concentrations of reagents are expressed as the final concentration in the reaction mixture. The test compounds are serially diluted with dimethylformamide, and 1.5 μL is added directly to the reaction mixture. After 30 min incubation at 37°C the reaction is terminated by addition of 400 μL of ethyl acetate and 100 μL of distilled water, then vortexed for 30 s and briefly centrifuged. Three hundred μLs of the organic phase is transferred to a new tube and evaporated until dry using nitrogen gas. The steroids are dissolved with 30 μL of ethyl acetate and the whole volume is applied to silica gel TLC plates. The substrate and the products (11-deoxycortisol and cortisol) are separated in the toluene-acetone (7:2) solvent system.