The pharmacology, pharmacokinetics and metabolism of a novel nonsteroidal selective androgen receptor modulator
Testosterone, an endogenous male hormone, is used exogenously to treat many disorders. However, there are many disadvantages to testosterone therapy, namely nonselective action, low oral bioavailability, and an unfavorable side-effects profile. This has led to the investigation of compounds that bypass these obstacles, known as selective androgen receptor modulators (SARMs). During in vitro studies in our laboratory, we discovered modifications to bicalutamide produced androgen agonist activity. These preliminary findings were used to synthesize a series of bicalutamide analogs and to determine if they possessed in vitro agonist activity. Additionally, in vivo pharmacologic studies were conducted in which we discovered the first nonsteroidal anabolic SARM. These studies identified the chemical modifications that increase binding to the androgen receptor (AR), AR-mediated transcriptional activation, and in vivo androgenic activity, which established the structure-activity relationships (SARs) leading to the development of S-4. Earlier investigations of compound R-1 showed metabolically conversion of this AR agonist to an antagonist through oxidation of the sulfur atom. In order to preserve the agonistic effect, an oxygen atom was substituted for the sulfur atom on the B ring of the molecule. Pharmacokinetic studies of oral and intravenous doses were conducted in beagle dogs and showed that S-4 had a shorter half-life than bicalutamide (4 hours versus 7 days), with a mean CL of 4.7 mL/min/kg and a mean Vss of 1.4 L/kg. S-4 also showed dose dependent oral bioavailability, with the highest bioavailability of 91% seen following a 0.1 mg/kg dose. The metabolism studies, using mass spectrometry, identified a number of phase I and phase II metabolites in the urine and feces of dogs and rats. A mass balance and disposition study was conducted using [C14 ] S-4 and showed that the major metabolite of S-4 was the hydrolysis product found in the urine, accounting for 25% of the injected dose. Approximately 32% of the dose was seen as parent compound in the feces. This may be due to biliary excretion of the glucuronide conjugates of S-4 or the parent drug itself. These studies showed that S-4 was extensively metabolized and excreted in both the urine and feces.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:aandrogen agonist sarm pharmacokinetics metabolism
Date of Publication:01/01/2003