10β,17α-Dihydroxyestra-1,4-dien-3-one: A Bioprecursor Prodrug Preferentially Producing 17α-Estradiol in the Brain for Targeted Neurotherapy

Abstract

Uterotrophic effect of 17α-estradiol, the C17 epimer of the main human estrogen 17β-estradiol, was shown to manifest in animal models at doses lower than those necessary for central outcome raising concerns about its potential to treat maladies of the central nervous system. We introduce here 10β,17α-dihydroxyestra-1,4-dien-3-one (α-DHED) that acts as a bioprecursor prodrug producing 17α-estradiol with remarkable selectivity to the brain and, therefore, without appreciable exposure of the periphery to the parent steroid. This distinguishing feature of α-DHED is shown by using an estrogen-responsive mouse model with complementary LC-MS/MS measurement of drug contents in target tissues. Our data warrant further research to fully establish the potential of α-DHED for a safe and efficacious 17α-estradiol-based neurotherapy.

Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug

“…(in cm) of the Franz diffusion chamber and dQ/dt denotes the steady-state slopes of linear plots of concentration in the receiving chamber (Q in pmol) versus time (t in h). In vitro metabolism studies were done according to our previously published protocol using fresh tissue homogenates (in pH 7.4 phosphate buffer) [ 22 , 33 , 34 ]. Briefly, freshly harvested tissues were immediately homogenized, warmed up at 35 °C for 5 min, then spiked with DHED (100 nmol/mL).…”

A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy

“…This ability prominently contributes to the overall beneficial effects of estrogens in the CNS. Our investigation on how estrogens can provide a “chemical shield” against free radicals [34] led us to the development of the very first preclinical CNS-selective estrogen therapy approach discussed here [35,36,37]. As shown in Figure 2, in this endeavor we have recognized that, upon direct hydroxyl radical ( • OH) capture, the phenolic A-ring of an estrogen undergoes oxidative dearomatization to para -quinol.…”

“…The latter is then rapidly reduced back by an enzyme-catalyzed process to the corresponding estrogen [35]. This antioxidant cycle essentially regenerates the hormone, which can then exerts its well-orchestrated genomic and non-genomic actions for curing, curtailing, or treating estrogen-responsive and centrally regulated maladies [26,36,37].…”

“…In spite of impressive basic science and translational preclinical data, as well as epidemiological observations showing the potential strength of E2-based neurotherapeutic interventions, clinical applications can only be realized when therapeutic actions are restricted specifically and selectively to the CNS to assure therapeutic safety [13,23,26,35,36,37]. Development of CNS-selective estrogen therapies, however, has to measure up to daunting challenges, and only prodrug strategies have delivered promising progress to achieve this goal thus far.…”

“…Targeted pharmacotherapy with prodrugs can only be achieved with site-directed delivery. This may be realized by, e.g., receptor-mediated enzyme prodrug systems, or site-specific facile bioactivation of the prodrug to the pharmacological active parent agent by enzymes preferentially expressed in the CNS [36,37,42,43]. An alternative strategy is to use promoieties that can undergo either reduction [44] or oxidation [45] to permanently-charged species within the brain to restrict their efflux back into the circulatory system, while these ionic species have been proposed to quickly excrete from the periphery by the renal route.…”