br Selective Androgen Receptor Modulators SARMs The AR and i

Selective Androgen Receptor Modulators (SARMs) The AR and its endogenous ligands, androgens, are important for development and maintenance of muscle and bone, secondary sexual organs, and development of other tissues (Mooradian et al., 1987). Although androgens are important for normal development of various tissues, under certain circumstances they also promote pathology of the prostate, heart, and the liver. Risks of YC 1 therapy such as dyslipidemia, benign prostatic hypertrophy, and uterine hyper-proliferation preclude its use. These pathological roles of testosterone and its 5α-reduced form (DHT) led to the search for tissue-selective agonists of the AR that could potentially activate the AR in selected tissues while sparing other tissues such as prostate, heart, and liver. Such an agonist would provide an opportunity to fully realize the therapeutic benefits of androgens. Most of the SARMs developed thus far are non-steroidal and have the ability to activate the AR in muscle and bone, without accompanying activation or minimal activation of the AR in prostate or seminal vesicles. In a similar vein, SARM development has also sought to overcome the potential virilizing effects of steroidal androgens (Holterhus et al., 2002). Considering that females, like males, are also affected by osteoporosis, sarcopenia, and cachexia, a non-virilizing SARM could treat these pathological states in women, without the virilizing side-effects accompanying steroidal androgens. The putative beneficial effects of testosterone therapy in certain female populations appear to be outweighed by the risks of virilization and poorly characterized cardiovascular risk. Recent clinical trials, although highlighting testosterone's ability to improve sexual function and muscle mass in older men, corroborated concerns that testosterone's cardiac risks outweighed its therapeutic benefits (Permpongkosol et al., 2016, Traish, 2016). Discovery of SARMs and structural diversity: Since the discovery of the first SARM in 1990s, several SARM scaffolds with diverse biological functions have emerged (Dalton et al., 1998). The first preclinical evidence for tissue-selective activation of the AR was that arylpropionamide SARMs increased levator ani muscle weight in castrated rats to the level of sham-operated rats, but only partially increased the prostate and seminal vesicles weight (Yin et al., 2003, Gao et al., 2005). This model, called the Hershberger assay, has been the primary means of demonstrating tissue selectivity in SARM discovery. The efficacy of SARMs in levator ani muscle in males and pelvic floor muscles in females have also been demonstrated in male orchiectomized and female ovariectomized mice (Dubois et al., 2015, Ponnusamy et al., 2017). Although the use of levator ani muscle as a surrogate end point for anabolic activity in skeletal muscle is criticized due to its unparalleled expression of the AR, it provides a sensitive and rapid assessment of anabolic effects. Over the next decade structure-activity relationship studies were conducted on the arylpropionamide class of SARMs that culminated in two clinical candidates, with enobosarm being the most advanced in clinical development (Gao et al., 2005, Srinath and Dobs, 2014). In addition to their effects on muscle, enobosarm and other arylpropionamide SARMs also demonstrated beneficial effects on bone (Kearbey et al., 2007). Enobosarm has been or is being evaluated in several phase II and phase III clinical trials for multiple indications such as cancer cachexia, sarcopenia, breast cancer, and stress urinary incontinence (Crawford et al., 2016, Dobs et al., 2013, Dalton et al., 2011). Ligand Pharmaceuticals developed tricyclic quinolinones that coincided with the discovery of arylpropionamide SARMs (Edwards et al., 1998, Higuchi et al., 1999). Similar to the arylpropionamide SARMs, these quinolinones also bind to and activate the AR in low nanomolar concentrations while eliciting tissue-selective activation of the AR in muscle.