A selective androgen receptor modulator with minimal prostate hypertrophic activity enhances lean body mass in male rats and stimulates sexual behavior in female rats

Abstract

Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-28330835 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle, stimulating maximal growth at a dose of 10 mg/kg. At the same time, JNJ-28330835 reduced prostate weight in intact rats by a mean of 30% at 10 mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging (MRI) to monitor body composition, it prevented half of the loss of lean body mass associated with orchidectomy, and restored about 30% of lost lean mass to aged orchidectomized rats. It had agonist effects on markers of both osteoclast and osteoblast activity, suggesting that it reduces bone turnover. In a model of sexual behavior, JNJ-28330835 enhanced the preference of ovariectomized female rats for sexually intact male rats over nonsexual orchidectomized males. JNJ-28330835 is a prostate-sparing SARM with the potential for clinically beneficial effects in muscle-wasting diseases and sexual function disorders.

Nonsteroidal Selective Androgen Receptor Modulators Enhance Female Sexual Motivation

“…Estrogen was administered to elicit sexual behavior; however progesterone is required to facilitate both proceptive and receptive behaviors (Erskine, 1989). Allan et al (2007) were the first to report the effectiveness of SARMs in female rats, showing that a pyrazoline-derived SARM was able to enhance a female's preference for sexually active males.…”

A selective androgen receptor modulator with minimal prostate hypertrophic activity restores lean body mass in aged orchidectomized male rats

“…Other investigators did not report assays in intact rats, so it is not clear how common is this property of JNJ-37654032. We have also observed mixed prostate agonism and antagonism with a series of pyrazoline SARMs [23,32].…”

“…5A and data not shown). Likewise, DHT increased fat mass in a separate study [32]. In contrast, TP and orchidectomy alone had no effect on fat mass.…”

Selective androgen receptor modulator activity of a steroidal antiandrogen TSAA-291 and its cofactor recruitment profile

“…Several groups recently discovered a structurally distinct class of orally active nonsteroidal compounds that exert weaker effects on the prostate while maintaining anabolic effects in muscle and the bone (Allan et al, 2007;Miner et al, 2007;Vajda et al, 2009). In the present study, we first observed that TSAA-291, a steroidal antiandrogen previously used to treat benign prostatic hyperplasia used in Japan, displayed partial agonist activity in reporter assays using COS-7 cells.…”

“…SARM is defined as compounds that specifically bind to the androgen receptor and exert agonistic/antagonistic effects in a tissue-specific manner (Negro-Vilar, 1999). SARM displaying tissue-selective anabolic effects in muscle and the bone without exerting adverse effects on prostate or latent prostate cancer would be a useful therapeutic option for sarcopenia, osteoporosis, muscle wasting associated with cancer cachexia, and aging-associated functional limitations (Allan et al, 2007;Miner et al, 2007).…”