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Dehydroepiandrosterone (DHEA) has attracted much interest because of its many antiaging, metabolic and immune-modulating effects in rodents. Synthetic derivatives, such as 5-androstene-16alpha-fluoro-17-one (HE2500) and certain natural metabolites also provide benefit in various animal models of autoimmune and metabolic diseases. But, like DHEA, low potency and low oral bioavailability suggested limited usefulness of these compounds in humans. We hypothesized that HE3286, a novel 17-ethynyl derivative would be orally bioavailable, more potent, and chemically more useful in man than its parent compound. We found that on a dose/mass basis, HE3286 demonstrated up to 25% oral bioavailability in mice. In the DBA mouse model of collagen-induced arthritis (CIA), animals receiving oral treatment with HE3286 (50 mg/kg), beginning at onset of disease, significantly decreased CIA peak scores and daily severity of arthritis scores. Benefit was associated with decreases in: (1) production of TNF-alpha, IL-6, and IL-17; and (2) decreases in joint inflammation, erosion, and synovial proliferation as judged by histological analysis. HE3286 was not found to be immune suppressive in any of the classical models tested, including mitogen-induced proliferation, delayed-type hypersensitivity, or mixed lymphocyte reaction. Instead, benefit was associated with increases in numbers and function of CD4+CD25+FOXp3+CD127- regulatory T cells (T reg). To our knowledge, this is probably the first study to report that an orally bioavailable synthetic analogue of DHEA can ameliorate ongoing disease in a CIA mouse model with relevance to rheumatoid arthritis (RA) and to correlate that finding with decreases in proinflammatory cytokines and increases in T reg cells. Hormones targeting T reg cells hold the intriguing potential to treat autoimmune, infectious, and neoplastic diseases.

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HE3286 (17alpha-ethynyl-5-androstene-3beta, 7beta, 17beta-triol) is a synthetic derivative of a natural anti-inflammatory steroid, beta-AET (5-androstene-3beta, 7beta, 17beta-triol). HE3286 is orally bioavailable and treats established disease in models of ulcerative colitis, collagen-induced arthritis, and collagen antibody-induced arthritis, reducing clinical signs of disease and proinflammatory signals, including IL-6 and matrix metallopeptidase 3. HE3286 modulates nuclear factor kappaB through an unknown mechanism but does not interact with any of the steroid-binding nuclear hormone receptors and is not immune suppressive. HE3286 was safe and well tolerated in phase I studies and is under evaluation in multicenter phase I/II clinical trials for ulcerative colitis and arthritis. HE3286 may provide a new treatment option for patients with inflammatory and autoimmune diseases.