IJCEM Copyright © 2008-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Clin Exp Med 2011;4(2):119-135

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

Clarence N. Ahlem, Michael R. Kennedy, Theodore M. Page, Christopher L. Reading, Steven K. White, John J. McKenzie, Phaedra I.
Cole, Dwight R. Stickney, James M. Frincke

Harbor BioSciences, Inc., 9171 Towne Centre Drive, Suite 180, San Diego, CA  92122, USA; MPI Research, 54943 North Main Street,
Mattawan, MI 49071, USA.

Received February 21, 2010; accepted April 19, 2011; Epub April 23, 2011; published May 15, 2011

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, 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. (IJCEM1102004).

Keywords: Toxicology, metabolism, pharmacokinetics, pharmacology, androstene, HE3286

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Address all correspondence to:
Clarence Ahlem, PhD
Harbor BioSciences, Inc.
9171 Towne Centre Drive, suite 180
San Diego, CA 92121
Tel: 858-320-2571
Fax: 858-558-6470