Pharmacology of selective androgen receptor modulators (SARMs)

The tissue selectivity of a new generation of selective androgen receptor modulators (SARMs) was characterized in castrated and intact male rats. Studies focused on two SARMs, S-1 and S-4. In castrated animals, SARMs showed strong agonist activity in the anabolic tissues by maintaining and/or restoring castration induced loss in levator ani muscle mass, soleus muscle strength, and total body bone mineral density; but weak agonist activity in maintaining and stimulating prostate growth. Although SARMs still worked as full agonists in the muscle of intact animals, S-1 and S-4 behaved as antagonists in the prostate with the presence of endogenous androgens. Furthermore, SARM also showed agonist activity in the pituitary, which could help maintain the feedback regulation of plasma LH and FSH levels. The tissue-selective agonist activity of SARMs in the anabolic tissues and the pituitary suggests that this novel class of nonsteroidal AR ligands might serve as better alternatives for male hormone replacement therapy and treatment of benign prostate hyperplasia (BPH).; Another significant advantage of SARMs, compared to steroidal ligands, is the oral bioavailability of this class of compounds. Pharmacokinetic studies showed that SARMs were orally available. In the castrated animal model, SARM also showed strong anabolic activity after oral administration, even more potent than oxandrolone, an orally available anabolic steroid, suggesting that SARM could also be used in the treatment of disease-related muscle wasting.; The mechanism underlying the tissue selectivity of SARMs was studied in detail. In vitro experiments using transiently expressed human 5alpha-reductase showed that SARMs were not substrates for 5alpha-reductase. Thus, 5alpha-reductase inhibition by SARMs could not contribute to the antagonist activity of SARM in the prostate in intact animals. The tissue selectivity of SARM was more related to the fact that testosterone activity in the prostate is amplified by conversion to dihydrotestosterone (DHT), a more potent androgen receptor agonist, while SARM activity was not amplified.; The other possible mechanism of action was the formation of active metabolites by liver metabolizing enzymes. In vitro and in vivo metabolism studies were conducted for S-4. The major metabolite identified was the B-ring deacetylation product of S-4. Although species differences were observed in S-4 metabolism due to the species difference in N-acetyltransferase expression, the metabolite was not active and could not contribute to the pharmacologic activity of S-4.; Gene expression profiling using a prostate cancer cell line, LNCaP, revealed the ligand-specific regulation of gene expression by S-4 as compared to DHT, suggesting that the tissue selectivity might not be simply due to the differences in the potency of these two ligands.; In conclusion, these SARMs, S-1 and S-4 demonstrated strong agonist activity in the muscle and pituitary, but weak agonist activity in the prostate with or without the presence of endogenous androgens. In vitro and in vivo studies showed that the tissue selective pharmacologic activity of SARMs was markedly different from steroidal androgens and could be related to the tissue specific expression of 5alpha-reductase and ligand-specific regulation of gene expression in the prostate.