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Selective Androgen Receptor Modulators (SARMs) are a class of androgen receptor

Purpose of review
The last decade has witnessed unprecedented discovery effort to develop selective androgen receptor modulators (SARMs) that improve physical function and bone health without adversely affecting the prostate and cardiovascular outcomes. This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity.

Recent Findings
While steroidal SARMs have been around since the 1940s, a number of nonsteroidal SARMs that do not serve as substrates for CYP19 aromatase or 5α-reductase, act as full agonists in muscle and bone and as partial agonists in prostate are in development. The differing interactions of steroidal and nonsteroidal compounds with AR contribute to their unique pharmacologic actions. Ligand binding induces specific conformational changes in the ligand binding domain, which could modulate surface topology and protein-protein interactions between AR and coregulators, resulting in tissue-specific gene regulation. Preclinical studies have demonstrated the ability of SARMs to increase muscle and bone mass in preclinical rodent models with varying degree of prostate sparing. Phase I trials of SARMs in humans have reported modest increments in fat-free mass.

Summary
SARMs hold promise as a new class of function promoting anabolic therapies for a number of clinical indications, including functional limitations associated with aging and chronic disease, frailty, cancer cachexia, and osteoporosis.

Keywords: SARMs, androgens, mechanisms of tissue selectivity, mechanisms of androgen action
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INTRODUCTION
Selective Androgen Receptor Modulators (SARMs) are a class of androgen receptor ligands that bind androgen receptor https://www.bodybuildersarms.com/ and display tissue-selective activation of androgenic signaling (1, 2). The initial efforts to develop steroidal SARMs, based on modifications of the testosterone molecule, date back to the 1940s. The modern era of nonsteroidal SARMs was unleashed by independent work at Ligand Pharmaceuticals (3–6) and the University of Tennessee (7, 8). The scientists at Ligand Pharmaceuticals were the first to develop a series of cyclic quinolinones that had anabolic activity on the skeletal muscle and some degree of tissue selectivity (3, 4, 9–13). The discovery by Dalton and Miller that aryl propionamides with structural similarities to bicalutamide and hydroxyflutamide could activate AR-dependent transcriptional activity provided the early lead for the development of diaryl propionamide class of SARMs (7, 8). The decade since these early efforts has witnessed the emergence of a large number of nonsteroidal SARMs from virtually all the major pharmaceutical companies (2). The review will focus on the rationale for SARM development, the molecular basis of androgen action, the mechanistic basis of tissue selectivity, and potential clinical applications for SARMs.

Rationale
Testosterone, the major ligand for androgen receptor, subserves a variety of physiologic functions in humans (14): it is essential for maintaining sexual function, germ cell development, and accessory sex organs. Testosterone also affects the skeletal muscle, fat, bone, hematopoeisis, coagulation, lipid, protein and carbohydrate metabolism, and psychosexual and cognitive behaviors. Although androgen deficiency in adult men is the most prevalent disorder of AR signaling (15), the major impetus for SARM development has come from the potential anabolic effects of these compounds on the skeletal muscle and bone.

As men and women grow old, they lose skeletal muscle mass, strength and power (16–20), mostly due to the preferential loss of type 2 muscle fibers (21). Age-associated loss of muscle mass and strength increases the risk of falls, fractures, mobility limitation, physical disability and poor quality of life (19, 22). Functional decline and dependence in older individuals place a large burden on health care services and costs. In spite of the high prevalence of functional limitations and disability among older individuals, the practicing geriatricians have few therapeutic choices for the treatment of older individuals with functional limitations and physical disability. Similarly, the course of many chronic illnesses, such as chronic obstructive lung disease, end stage renal disease, congestive heart failure, and some types of cancer, is punctuated by loss of muscle mass and physical functional limitations, which contribute independently to symptoms, mobility limitation, and disability. Thus, there is an enormous unmet need for function promoting anabolic therapies that can improve physical function and reduce the burden of disability. Among the various candidate function promoting anabolic therapies that are in development, SARMs are the farthest along the developmental course.

Testosterone supplementation increases skeletal muscle mass and maximal voluntary strength in healthy, androgen-deficient (23–26) and eugonadal young (27, 28) and older men (29), and in men with many chronic disorders (30, 31). The anabolic effects of testosterone on skeletal muscle mass and strength are related to testosterone dose and its circulating concentrations (28, 29, 32, 33). Thus, the potential to achieve skeletal muscle remodeling and gains in skeletal muscle mass and strength with androgen supplementation is substantial. However, administration of supraphysiologic doses of androgens is associated with high frequency of dose-limiting adverse effects, such as erythrocytosis, leg edema, and prostate events (29, 34). Therefore, therapeutic agents such as SARMs that can achieve anabolic effects on the skeletal muscle and bone without the dose-limiting adverse effects associated with testosterone would be attractive as function promoting anabolic therapies (1, 2, 6). The recognition of these potential opportunities for the development of novel therapies for functional limitations and disability associated with chronic disorders and aging, and osteoporosis has driven the pharmaceutical efforts to develop SARMs.

Achieving Tissue Selectivity
Two general approaches have historically been used to achieve tissue selectivity of androgen action. The first approach is to develop SARMs with the desired activity profile and tissue selectivity. The second approach is to elucidate the mechanisms of androgen action on the skeletal muscle and the prostate and to identify signaling molecules that are downstream of androgen receptor and which activate pathways involved in skeletal muscle hypertrophy, but not the prostate.

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