A synthetic anti-inflammatory sterol improves insulin sensitivity in insulin-resistant obese impaired glucose tolerance subjects.

Objective: To study the activity of HE3286 (17α-ethynylandrost-5-ene-3β,7β,17β-triol), an anti-inflammatory sterol that is active in models of obesity-induced inflammation and insulin resistance in high body mass index (BMI) subjects with impaired glucose tolerance (IGT).

Design And Methods: HE3286 was explored in high BMI IGT subjects using hyperinsulinemic, euglycemic clamp studies.

Results: In insulin-resistant subjects, HE3286 significantly increased day 29 insulin-stimulated glucose disposal and HDL cholesterol, and decreased C-reactive protein (CRP) compared to placebo.

17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson's Disease.

17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) is a synthetic androstenetriol in Phase II clinical development for the treatment of inflammatory diseases. HE3286 was evaluated for blood-brain barrier (BBB) permeability in mice, and efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease (PD). We found that HE3286 freely penetrated the BBB.

Molecular targets for 17α-ethynyl-5-androstene-3β,7β,17β-triol, an anti-inflammatory agent derived from the human metabolome.

HE3286, 17α-ethynyl-5-androstene-3β, 7β, 17β-triol, is a novel synthetic compound related to the endogenous sterol 5-androstene-3β, 7β, 17β-triol (β-AET), a metabolite of the abundant adrenal steroid dehydroepiandrosterone (DHEA). HE3286 has shown efficacy in clinical studies in impaired glucose tolerance and type 2 diabetes, and in vivo models of types 1 and 2 diabetes, autoimmunity, and inflammation. Proteomic analysis of solid-phase HE3286-bound bead affinity experiments, using extracts from RAW 264.

17α-ethynyl-5α-androstane-3α, 17β-diol treatment of MNU-induced mammary cancer in rats.

N-methyl-N-nitrosourea (MNU) induces estrogen-dependent mammary tumors in female Lewis rats. We explored the antineoplastic activity of a synthetic androstane derivative, 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235), as a single agent or in combination with docetaxel compared to tamoxifen, anastrazole, and docetaxel monotherapies against MNU-induced mammary tumors in female Lewis rats. Treatment with HE3235 alone rapidly reduced tumor burden, similar in effect to tamoxifen and anastrozole.

Studies of the pharmacology of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol, a synthetic anti-inflammatory androstene.

17α-Ethynyl-androst-5ene-3β, 7β, 17β-triol (HE3286) is an orally bioavailable analogue of androst-5-ene-3β,7β,17β-triol, a non-glucocorticoid anti-inflammatory metabolite of the adrenal steroid, dehydroepiandrosterone. The pharmacology of HE3286 was characterized in preparation for clinical trials in type 2 diabetes mellitus and other diseases of inflammation. Interactions with nuclear hormone receptors and P450 enzymes were measured in vitro.

Phase I and Phase II clinical trials of androst-5-ene-3β,7β,17β-triol.

Unlabelled: The immune regulating DHEA metabolite, androst-5-ene-3β,7β,17β-triol (βAET), was evaluated for safety, cholesterol lowering, and vaccine enhancement in phase I and phase II clinical trials. Safety and pharmacokinetics were evaluated in one study of normal subjects that received βAET or placebo transmucosally (buccal tablets) for 4 days. In a second study βAET was given by daily subcutaneous injection for 3 days.

Pharmacology and immune modulating properties of 5-androstene-3β,7β,17β-triol, a DHEA metabolite in the human metabolome.

Androst-5-ene-3β,7β,17β-triol (βAET) is an anti-inflammatory metabolite of DHEA that is found naturally in humans, but in rodents only after exogenous DHEA administration. Unlike DHEA, C-7-oxidized DHEA metabolites cannot be metabolized into potent androgens or estrogens, and are not peroxisome proliferators in rodents. The objective of our current studies was to characterize the pharmacology of βAET to enable clinical trials in humans.

HE3286, an orally bioavailable synthetic analogue of an active DHEA metabolite suppresses spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse.

5-Androstene-3β,7β,17β-triol (AET) is a naturally occurring anti-inflammatory adrenal steroid that limits acute and chronic inflammation. HE3286 (17α-ethynyl-5-androstene-3β,7β,17β-triol) is a synthetic derivative of AET with improved pharmaceutical properties and efficacy in some animal models of autoimmunity. Here, daily oral doses of HE3286 led to a suppression of spontaneous autoimmune diabetes in the non-obese diabetic mouse model of type 1 diabetes mellitus when administered either shortly before or after the first incidence of disease onset.

5-androstenediol ameliorates pleurisy, septic shock, and experimental autoimmune encephalomyelitis in mice.

Androstenediol (androst-5-ene-3β,17β-diol; 5-AED), a natural adrenal steroid, has been shown to suppress experimental autoimmune encephalomyelitis (EAE) in female SJL/J mice. We here report that 5-AED limits inflammation and proinflammatory cytokines including TNFα in murine models of carrageenan-induced pleurisy and lippopolysaccaride- (LPS) induced septic shock. 5-AED binds to and transactivates sex steroid receptors with the same general rank order of potency (ERβ > ERα ≫ AR).

5-Androstene-3β,7β,17β-triol (β-AET) slows thermal injury induced osteopenia in mice: relation to aging and osteoporosis.

5-Androstene-3β,7β,17β-triol (β-AET), an active metabolite of dehydroepiandrosterone (DHEA), reversed glucocorticoid (GC)-induced suppression of IL-6, IL-8 and osteoprotegerin production by human osteoblast-like MG-63 cells and promoted osteoblast differentiation of human mesenchymal stem cells (MSCs). In a murine thermal injury model that includes glucocorticoid-induced osteopenia, β-AET significantly (p<0.05) preserved bone mineral content, restored whole body bone mineral content and endochondral growth, suggesting reversal of GC-mediated decreases in chondrocyte proliferation, maturation and osteogenesis in the growth plate.

HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression.

Background: 17α-Ethynyl-5-androsten-3β, 7β, 17β-triol (HE3286) is a synthetic derivative of an endogenous steroid androstenetriol (β-AET), a metabolite of the abundant adrenal steroid deyhdroepiandrosterone (DHEA), with broad anti-inflammatory activities. We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact.

Methods And Results: In mice, oral treatment with HE3286 (40 mg/kg) significantly (p < 0.

Novel components of the human metabolome: the identification, characterization and anti-inflammatory activity of two 5-androstene tetrols.

Two natural 5-androstene steroid tetrols, androst-5-ene-3β,7β,16α,17β-tetrol (HE3177) and androst-5-ene-3α,7β,16α,17β-tetrol (HE3413), were discovered in human plasma and urine. These compounds had significant aqueous solubility, did not bind or transactivate steroid-binding nuclear hormone receptors, and were not immunosuppressive in murine mixed-lymphocyte studies. Both compounds appear to be metabolic end products, as they were resistant to primary and secondary metabolism.

A potential role for 5-androstene-3β,7β,17β-triol in obesity and metabolic syndrome.

Metabolic syndrome is marked by perturbed glucocorticoid (GC) signaling, systemic inflammation, and altered immune status. Dehydroepiandrosterone (DHEA), a major circulating adrenal steroid and dietary supplement, demonstrates antiobesity, anti-inflammatory, GC-opposing and immune-modulating activity when administered to rodents. However, plasma DHEA levels failed to correlate with metabolic syndrome and oral replacement therapy provided only mild benefits to patients.

Oral treatment with HE3286 ameliorates disease in rodent models of rheumatoid arthritis.

HE3286 (17alpha-ethynyl-5-androstene-3beta, 7beta, 17beta-triol) is an orally bio-available synthetic derivative of naturally occurring androstene-3beta, 7beta, 17beta-triol. Our present data show that oral treatment with HE3286, favourably influenced the course of arthritis in the rat model of adjuvant-induced arthritis (reduced cumulative disease scores and paw edema), and in the mouse model of collagen antibody-induced arthritis (reduced clinical paw scores). Importantly, HE3286 was not immune suppressive in human mixed lymphocyte reaction or in animals challenged with Coxsackie B3 virus.

An orally bioavailable synthetic analog of an active dehydroepiandrosterone metabolite reduces established disease in rodent models of rheumatoid arthritis.

Dehydroepiandrosterone (DHEA) treatment provides diverse anti-inflammatory benefits in rodent models of diseases, including rheumatoid arthritis (RA), but only limited benefits to patients. In rodents, DHEA is metabolized to (among others) androstene-3beta,7beta,17beta-triol (AET), which retains potent anti-inflammatory activity. 17Alpha-ethynyl-5-androstene-3beta,7beta,17beta-triol (HE3286) is a novel, metabolically stabilized, orally bioavailable derivative of AET.

7-Hydroxy androstene steroids and a novel synthetic analogue with reduced side effects as a potential agent to treat autoimmune diseases.

The metabolome of dehydroepiandrosterone (DHEA), the most abundant adrenal steroid in the human body, includes androgens, estrogens and a series of immune regulating hormones that lack androgenic or estrogenic activity. Of these, 7-hydroxy derivatives, once considered physiologically inactive end products of metabolism, possess a combination of potent anti-inflammatory and immune modulating activity without androgenic or estrogenic capacity. Oxygenated metabolites derived from androstenediol (AED), the predominant precursor in rodents, may be responsible for many activities initially attributed to exogenous DHEA administered to rodents.

A synthetic androstene analogue inhibits collagen-induced arthritis in the mouse.

Dehydroepiandrosterone (DHEA), a precursor of immune-regulating hormones (IRH) including the androstenes, has attracted much interest over the last several decades because of its many antiaging, metabolic, and immune modulating effects. 5-Androstene-16alpha fluoro-17-one (fluasterone, also known as HE2500) is a synthetic androstene analogue that retains anti-inflammatory, antiproliferative, and immune-regulating activities of the parent molecule, but is nontoxic and practically devoid of androgenic or estrogenic side effects. In the present studies, we tested the ability of fluasterone to limit disease in the DBA mouse model of collagen-induced arthritis (CIA).

A synthetic androstene derivative and a natural androstene metabolite inhibit relapsing-remitting EAE.

Experimental allergic encephalomyelitis (EAE), a Th1 polarized demyelinating disease of the central nervous system (CNS), shares many pathological and clinical similarities with multiple sclerosis (MS), and thus represents an attractive animal model for this disease. The goal of this study was to evaluate the suppressive effects of fluasterone (HE2500), a synthetic androstene derivative, and androstenetriol (HE2200), a natural androstene hormone on EAE. SJL mice were immunized with proteolipid protein (PLP) 139-151 peptide/CFA to induce EAE.