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

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Ahlem CN, Kennedy MR, Page TM, Reading CL, White SK, McKenzie JJ, Cole PI, Stickney DR, Frincke JM

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

Int J Clin Exp Med. 2011;4(2):119-35. Epub 2011 Apr 23.

PubMed ID

21686136 [ View in PubMed

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Abstract

17alpha-Ethynyl-androst-5ene-3beta, 7beta, 17beta-triol (HE3286) is an orally bioavailable analogue of androst-5-ene-3beta,7beta,17beta-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. Drug metabolism was studied preclinically in mice, rats, dogs, and monkeys. Neurological and cardiopulmonary safety and dose-ranging and chronic toxicity studies were conducted in rats and dogs in accordance with FDA guidelines. Pharmacokinetics and metabolites were measured in Phase I clinical trials. HE3286 was differentially metabolized between species. HE3286 and metabolites did not bind or transactivate steroid binding nuclear hormone receptors or inhibit P450 enzymes. There were no adverse effects in safety pharmacology and canine toxicology studies. Although HE3286 did not elicit systemic toxicity in rats, mild estrogenic effects were observed, but without apparent association to hormonal changes. Safety margins were greater than 20-fold in rats and dogs with respect to the most commonly used clinical dose of 10 mg/day. The terminal half-life in humans was 8 hours in males and 5.5 hours in females. HE3286 is the first derivative of the DHEA metabolome to undergo a comprehensive pharmacological and safety evaluation. The results of these investigations have shown that HE3286 has a low potential for toxicity and possesses pharmacological properties generally suitable for use in human medicine. The favorable profile of HE3286 warrants further exploration of this new class of anti-inflammatory agents.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
HE3286	Cytochrome P450 3A4	Protein	Humans	No	Substrate	Details