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  • Compounds are representatives of an array of MBG targets

    2024-05-15

    Compounds – are representatives of an array of MBG targets (, ) related to imidazole standard that were synthesized and initially tested in a rat CYP17 lyase screening assay (). The inhibitors were synthesized as racemates by coupling of 6,7-dimethoxy-naphthalene-2-isopropyl ketone with the requisite lithiated heterocycle in modest yields (15–65%; )., Heteroaromatic MBGs were selected that encompassed a wide range of basicities though emphasis was placed on low-affinity moieties that might demonstrate selectivity for rat CYP17 lyase versus the metabolic human enzyme CYP3A4. As shown in , the oxazole and 4-pyridine furnished adequate lyase potency (ICs of 86 and 60nM) but both inhibited CYP3A4 as well (ICs <10μM). An MBG that exhibited threshold potency (IC=0.18μM) and markedly enhanced selectivity over CYP3A4 (317-fold) was the 4-(1,2,3-triazole) . This promising MBG was selected for further optimization within the naphthalene chemical series. Triazole exhibited equal potency for rat and human CYP17 lyase (IC=0.18μM) and was selected for further optimization through scaffold modifications to achieve the following thresholds: h-CYP17 lyase potency IC <0.2μM, h-CYP17 lyase/hydroxylase selectivity >10-fold, and selectivity >50-fold for h-CYP17 lyase versus h-CYP3A4. Representative 4-(1,2,3-triazoles) – containing a variety of substituents () at the 6- and 7-positions were synthesized and tested for human lyase, human hydroxylase, and CYP3A4 potency in comparison to imidazole (). Several molecules in this chemical series (, , ) exhibited improved lyase selectivity versus hydroxylase and CYP3A4 (H/L and 3A4/L ratios, ) compared to the literature 1-imidazole (). While exhibited good lyase potency and promising selectivity it was not evaluated further due to poor human liver microsome stability (29% parent remaining after 60min compared to 54% remaining for ). Racemic MK-4827 hydrochloride mg , an analogue of , furnished superior lyase potency and selectivity. Though the active enantiomer of also exhibited excellent selectivity, it furnished inferior lyase potency compared to racemic ( enantiomer IC data not shown). The enantiomers of were synthesized and isolated according to . Briefly, 6,7-dimethoxy-naphthyl-isopropyl ketone was demethylated under strongly-acidic conditions (boron tribromide) and the resultant -dihydroxy-naphthalene intermediate then capped with two difluoromethyl groups using standard base-mediated α-bromo-difluoroacetate conditions to furnish intermediate . Ketone was then converted to by sequential addition of lithiated 1--SEM-triazole and subsequent SEM removal with fluoride. Resolution of the antipodes of using chiral HPLC provided a potent CYP17 lyase inhibitor that demonstrated both exceptional in vitro lyase/hydroxylase selectivity (∼10-fold), and oral activity in a hamster model of androgen biosynthesis inhibition ()., Inhibitor and the comparator compounds abiraterone acetate (AA), an approved CYP17 inhibitor, and the active imidazole , were evaluated for their effects on steroid biosynthesis in hamster following a single 50mg/kg oral dose., All three CYP17 inhibitors significantly decreased plasma testosterone concentrations to the lower limit of quantitation (LLOQ) 2h post-dose (). However, administration of the 3-pyridine, AA, and the imidazole produced a statistically-significant increase in plasma progesterone, a marker for CYP17 hydroxylase inhibition. In contrast, triazole administration produced only a modest increase in progesterone consistent with its superior in vitro CYP17 lyase/hydroylase selectivity. Similar in vivo effects on testosterone and progesterone following oral administration of and AA were observed in castrate monkeys. In summary, we have described the design, synthesis, and discovery of novel 4-(1,2,3-triazole)-based CYP17 lyase-selective inhibitors. An orally active representative from this chemical series, VT-464 (), is in clinical development for the treatment of patients with castration-refractory prostate cancer. The MBG-based design process described herein was used to produce the most lyase-selective CYP17 inhibitors reported to date, including the potent oral clinical agent . The process is generalizable and broadly applicable to the design and evaluation of new and improved chemical entities within the metalloenzyme inhibitor class.