Pharmacology, pharmacokinetics and metabolism of nonsteroidal androgens

Nonsteroidal androgens represent a novel class of agents with a wide variety of potential therapeutic applications. The goal of present studies was to develop in vivo functional nonsteroidal androgens.; We assessed the androgen receptor (AR) binding properties of multiple series of nonsteroidal compounds derived from known antiandrogens, using a radioligand competitive binding assay. These compounds demonstrated a wide range of binding affinity for the AR. A number of compounds showed binding affinity superior to their lead antiandrogens.; We tested the in vitro functional activities of a set of bicalutamide-based AR ligands, using a co-transfection assay. The activity profiles of test ligands covered antagonist, partial agonist, and full agonist for the AR.; Next, we evaluated the pharmacological activity of acetothiolutamide, an AR full agonist identified by in vitro studies, in a castrated immature rat model. In this model, acetothiolutamide exhibited negligible andrognic activity, and noticeable anabolic and antiandrogenic activities.; Subsequently, we examined the pharmacokinetics of acetothiolutamide in rats. Acetothiolutamide was rapidly cleared from plasma after intravenous dosing. Acetothiolutamide was completely absorbed following subcutaneous administration, but was not bioavailable after oral dose. The high plasma clearance of acetothiolutamide was likely a reason for its lack of androgenic activity in rats. Also, acetothiolutamide was highly bound to rat plasma proteins.; We characterized the metabolite profiles of acetothiolutamide in rats, using LC-MS and LC-MS/MS techniques. Acetothiolutamide was excreted in urine and feces as unchanged drug and a variety of metabolites. Oxidation, hydrolysis, and sulfate conjugation were the major metabolic pathways. The extensive hepatic metabolism of acetothiolutamide likely contributes to its high clearance in rats.; Based upon knowledge from the studies described above, we designed and synthesized acetoxolutamide. Acetoxolutamide displayed high AR binding affinity and full AR agonist activity in the in vitro assays. In immature castrated rats, acetoxolutamide showed efficacious androgenic and preferential anabolic activities.; In conclusion, our studies provided insights into the SARs regarding nonsteroidal AR binding and agonist activity. More significantly, we discovered acetoxolutamide, an efficacious nonsteroidal androgen with preferential anabolic activity in vivo. This achievement represents a major advance towards the ultimate development of a new generation of androgens.