Nuclear receptors (NRs) are a class of structurally related proteins that modulate gene expression by acting as ligand-dependent transcription factors [Evans, R. M. Science 1988, 240, 889-95]. The steroid receptors, namely the androgen receptor (AR), the estrogen receptor (ER), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the progesterone receptor (PR) represent a subclass of the nuclear receptor superfamily. NR ligands in this subclass exert their effects by binding to an intracellular steroid hormone receptor. In the presence of an agonist ligand the AR binds as a homodimer to the androgen response element (ARE), a consensus sequence for steroid receptors (GGTACAnnnTGTTCT) [Beato M. Cell 1989, 56, 335-44. Cato, A. C. B. and Peterziel, H. TEM 1998, 9, 150-154. Wong, C. I.; Zhou, Z. X.; Sar, M.; Wilson, E. M. J. Biol. Chem. 1993, 268, 19004-12].
Certain NR ligands are known to exert their action in a tissue selective manner [Smith, C. L.; O'Malley, B. W. Endoc. Rev. 2004, 25, 45-71]. This selectivity stems from the particular ability of these ligands to function as agonists in some tissues, while having no effect or even an antagonist effect in other tissues. The term “selective receptor modulator” (SRM) has been given to these molecules. A synthetic compound that binds to an intracellular receptor and mimics the effects of the native hormone is referred to as an agonist. A compound that inhibits the effect of the native hormone is called an antagonist. The term “modulators” refers to compounds that have a spectrum of activities ranging from full agonism to partial agonism to full antagonism.
Steroidal NR ligands are known to play important roles in the health of both men and women. In regard to men's health, testosterone (T) and dihydrotestosterone (DHT) are endogenous steroidal ligands for the AR that likely play a role in every tissue type found in the mammalian body. During the development of the fetus, androgens play a role in sexual differentiation and development of male sexual organs. Further sexual development is mediated by androgens during puberty. Androgens play diverse roles in the adult including stimulation and maintenance of male sexual accessory organs and maintenance of the musculoskeletal system. Cognitive function, sexuality, aggression, and mood are some of the behavioral aspects mediated by androgens. Androgens affect the skin, bone, and skeletal muscle, as well as blood lipids and blood cells [Chang, C. 2002, 503 pp. Publisher: (Kluwer Academic Publishers, Norwell, Mass.)].
The study of androgen action and male reproductive dysfunction continues to expand significantly. In fact, only recently has the definition of a disease state been associated with hormonal changes that occur in aging men. This syndrome, previously referred to as “Andropause,” has more recently been described as Androgen Deficiency in the Aging Male, or “ADAM” [Morales, A. and Tenover, J. L. Urologic Clinics of North America 2002, 29, 975]. The onset of ADAM is unpredictable and its manifestations are subtle and variable. Clinical manifestations of ADAM include fatigue, depression, decreased libido, erectile dysfunction as well as changes in cognition and mood.
Published information indicates that androgen replacement therapy (ART) in men may have benefits in terms of improving body composition parameters (e.g. bone mineral density, lean muscle mass, and strength) as well as improving libido and mood in some men. Andrologists and other specialists are increasingly using ART for the treatment of the symptoms of ADAM. This use is with due caution given potential side effects of androgens. Nonetheless, there is increasing scientific rationale and evidence for androgen deficiency and treatment in the aging male
In general, current ARTs fail to correctly mimic physiological testosterone levels and have potential side effects including exacerbation of pre-existing sleep apnoea, polycythemia (increased hematocrit), and/or gynaecomastia. Furthermore, the longer-term side effects on target organs such as the prostate or the cardiovascular system are yet to be fully elucidated. Importantly, the potential cancer promoting effects of testosterone on the prostate prevent many physicians from prescribing it to older men (i.e. age >60 years) who, ironically, stand to benefit most from treatment. The need for a novel selective androgen receptor modulator (SARM) is obviated by the potential side effect profile manifested by conventional treatments. An ideal SARM has all the beneficial effects of endogenous androgens, while sparing sexual accessory organs, specifically the prostate.
SARMs are currently in the early stages of development. Much of the preclinical and clinical understanding of the therapeutic promise of SARMs stems from work using anabolic steroids. Because of their highly selective anabolic properties and demonstrated prostate sparing activity, SARMs could be used for prevention or treatment of many diseases, including, but not limited to sarcopenia (muscle wasting), osteoporosis, frailty, and other conditions associated with aging or androgen deficiency. SARMs also show promise in the areas of hormonal male contraception and benign prostatic hyperplasia (BPH). The therapeutic potential of SARMs for treatment of androgen deficient disorders in women is a far less studied field. This review primarily focuses on the use of SARMs for the treatment and prevention of disease in males, but many of these therapies could apply to both genders.
Male hypogonadism represents a state of impaired testosterone production. There are two general types of hypogonadism: primary hypogonadism is due to testicular failure, while secondary hypogonadism is due to malfunction at the hypothalamic/pituitary level. Gonadotropins can be elevated or decreased depending on the localization of the condition. Severe symptoms are associated with the hypogonadal state. Symptomatic profiles differ depending on the time of onset of the condition. Symptoms in patients who experience hypogonadism after normal virilization include decreased muscle mass, osteopenia/osteoporosis, decreased fertility, increased visceral fat, and sexual dysfunction [Zitzmann, M.; Nieschlag, E. Mol. Cell. Endo. 2000, 161, 73-88].
A SARM in hypogonadal men would provide the anabolic effects of testosterone with the convenience of oral administration. Prostate drive is usually not a concern for young hypogonadal males, but the sparing effects of a SARM may still prove beneficial. Clinical studies in hypogonadal males using testosterone have provided compelling efficacy data [Wang, C.; Cunningham, G.; Dobs, A.; Iranmanesh, A.; Matsumoto, A. M.; Synder, P. J.; Weber, T.; Berman, N.; Hull, L.; Swerdloff, R. S. J. Clin. Endo. Met. 2004, 89, 2085-2098].
Over 80% of all illness, morbidity, and medical costs are concentrated in the years after age 65. With increased survival to more advanced ages, the absolute numbers of senior citizens will increase markedly in coming years. According to the United Nations World Health Organization report on Aging, it is anticipated that by 2030 one in five American will be over the age of 65 [Anonymous, Centers for Disease Control and Prevention (CDC) MMWR Trends in Aging—United States and Worldwide. Morbidity and Mortality Weekly Report 2003, 52, 101-4, 106]. Though decline in organ function is inevitable in this population, it may be possible to extend organ function, thereby increasing quality of life (QOL) in older people. Therapeutic interventions that reduce organ decline and increase QOL will clearly be widely accepted, both for their ability to decrease overall health care costs and to improve the length of functional life.
Clinical studies show that ART in men improves body composition parameters such as muscle mass, strength, and bone mineral density [Asthana, S.; Bhasin, S.; Butler, R. N.; Fillit, H.; Finkelstein, J.; Harman, S. M.; Holstein, L.; Korenman, S. G.; Matsumoto, A. M.; Morley, J. E.; Tsitouras, P.; Urban, R. J. Ger., Series A: Biol. Sci. Med. Sci. 2004, 59, 461-465]. There is also evidence of improvement in less tangible parameters such as libido and mood. Andrologists and other specialists are increasingly using androgens for the treatment of the symptoms of androgen deficiency. ART, using T and its congeners, is available in transdermal, injectable and oral dosage forms. All current treatment options have contraindications (e.g., prostate cancer) and side-effects, such as increased hematocrit, liver toxicity, and sleep apnoea.
Sarcopenia or muscle wasting is the aging-associated decline in neuromuscular function and performance [Lynch, G. S. Exp. Opin. Emerg. Drugs 2004, 9, 345-361]. Skeletal muscle atrophy and weakness are considered major contributing factors to the loss of mobility, independence, and frailty that affect many older adults [Doherty, T. J. J. App. Phys. 2003, 95, 1717-1727]. Relative muscle loss in aging men and women is similar, but because men start with higher baseline values, their absolute loss of strength is greater. Epidemiological data support the relationship between the fall in testosterone and the decline in muscle mass [Janssen, I.; Shepard, D. S.; Katzmarzyk, P. T.; Roubenoff, R. JAGS 2003, 80-85. Baumgartner, R. N.; Waters, D. L.; Gallagher, D.; Morley. J. E.; Garry, P. J. Mechanisms of Ageing and Development 1999, 107, 123-36]. As mentioned above, many clinical studies with testosterone have demonstrated significant gains in muscle mass and function along with decreases in visceral fat [Bhasin, S. J. Gerontol. A Biol. Sci. Med. Sci. 2003, 58, 1002-1008. Ferrando, A. A.; Sheffield-Moore, M.; Yeckel, C. W.; Gilkison, C.; Jiang, J.; Achacosa, A.; Lieberman, S. A.; Tipton, K.; Wolfe, R. R.; Urban, R. J. Am. J. Phys. Endo. Met. 2002, 282, E601-E607].
The actual mechanisms of androgen-promoted muscle anabolism are still not fully understood. It is generally believed that androgen-induced increases in muscle mass can be attributed to increases in muscle protein synthesis [Brodsky, I.; Balagopal, P.; Nair, K. J. Clin. Endocrinol. Metab. 1996, 81, 3469-3475]. Muscle size increases associated with androgen therapy occur through the hypertrophy of both type I and type II muscle fibers. Studies have shown that androgens promote increases in satellite cell number as well as myonuclei [Singh, R.; Artaza, J, N.; Taylor, W. E.; Gonzalez-Cadavid, N. F.; Bhasin, S. Endocrinology 2003, 144, 5081-5088]. Other studies have shown androgens to promote the commitment of pluripotent, mesenchymal cells into the myogenic lineage and to inhibit differentiation into the adipogenic lineage.
Men undergo a gradual reduction in bone mass in early to mid adulthood. In fact, when in their late 60's, men lose bone mass at a rate similar to women. There is increasing evidence that T plays an important role in the maintenance of bone [Notelovitz, M. Fertil. Steril. 2002, 77, S34-S41. Vanderschueren, D.; Vandenput, L. Andrologia 2000, 32, 125-30]. There have been multiple studies examining the relationship between bone mineral density (BMD) and related bone markers and T levels in men. Osteoporosis is common in men undergoing treatment for prostate cancer. Bilateral orchidectomy and gonadotropin-releasing hormone agonist treatment decrease BMD and increase fracture risk [Smith, M. R. Cancer and Meta. Rev. 2002, 21, 159-166]. Testosterone therapy increases bone mineral density in men with low T [Leifke, E.; Korner, H. C.; Link, T. M.; Behre, H. M.; Peters, P. E.; Nieschlag, E. Eur. J. Endocrinol. 1998, 138, 51-58. Schubert, M.; Bullmann, C.; Minnemann, T.; Reiners, C.; Krone, W.; Jockenhoevel, F. Hormone Research 2003, 60, 21-28]. It is not entirely clear if both T and E2 are required for healthy bone maintenance. A combination therapy of estrogen and androgen increases BMD to a greater extent than does estrogen therapy alone [Vanderschueren, D.; Vandenput, L. Andrologia 2000, 32, 125-30].
Androgens are important for skeletal homeostasis, affecting bone mineral density (BMD) by regulating the bone breakdown and remodeling process. Androgen action on AR expressing osteoblasts inhibits osteoclastogenesis in the bone marrow cavity. Androgens increase cortical bone formation mainly by stimulating periosteal bone formation [Notelovitz, M. Fertil. Steril. 2002, 77, S34-S41].
Clinically employed antiresorptive therapies such as estrogen replacement, selective estrogen receptor modulators (SERMs), bisphosphonates, and cathepsin K inhibitors, do not restore bone mass in patients already showing significant bone loss. The clinical use of intermittent parathyroid hormone (PTH) treatment to promote bone formation is limited because of side effects and possible association with osteosarcoma. Like T therapy, SARMs offer promise not only as antiresorptive agents, but also as osteoanabolic agents. A few preclinical studies demonstrating the promise of SARMs in the treatment of osteoporosis have been published [Hanada, K.; Furuya, K.; Yamamoto, N.; Nejishima, H.; Ichikawa, K.; Nakamura, T.; Miyakawa, M.; Amano, S.; Sumita, Y.; Oguro, N. Biol. Pharm. Bull. 2003, 26, 1563-1569. Rosen, J. and Negro-Vilar J. Musc. Neur. Interact. 2002, 2, 222-224. Kearbey, J. D.; Gao, W.; Miller, D. D.; and Dalton, J. T. Pharm. Sci. 2003, 5, R61-R67]. SARMs were shown to significantly increased BMD and bone strength in ORX rats [Hanada, K.; Furuya, K.; Yamamoto, N.; Nejishima, H.; Ichikawa, K.; Nakamura, T.; Miyakawa, M.; Amano, S.; Sumita, Y.; Oguro, N. Biol. Pharm. Bull. 2003, 26, 1563-1569]. Administration of the SARM, S-40503, to ORX rats for 4 weeks increased bone mineral density (BMD) of femur and levator ani muscle weight as markedly as DHT. Prostate weight was not elevated over that for eugonadal rats at any doses tested. In order to further validate the bone anabolic effect, S-40503 was given to ovariectomized (OVX) rats over a 2 month period. The SARM significantly increased BMD and biomechanical strength of femoral cortical bone, whereas the antiresorptive estrogen did not An increase in periosteal mineral apposition rate of the femur showed direct bone formation activity of S-40503. The increase in BMD was not attributed to muscle anabolism as hind limb suspended rats showed like increases in BMD.
Benign prostatic hyperplasia (BPH) affects the majority of men in the United States over the age of 50. Prostatic drive is determined by the local concentration of androgen. DHT, the androgen of the prostate, is produced in the prostate by the action 5-α-reductase on T. BPH can lead to many problems including acute urinary retention, recurrent bladder infection, bladder calcul, and a general decrease in a patient's quality of life [Kirby, R. S. Urology 2000, 56, 3-6. Andriole, G.; Bruchovsky, N.; Chung, L. W. K.; Matsumoto, A. M.; Rittmaster, R.; Roehrborn, C.; Russell, D.; Tindall, D. J. of Urology 2004, 172, 1399-1403. Djavan, B.; Barkin, J. European Urology, Supplements 2003, 2, 20-26].
SARMs that compete with prostatic binding of DHT, but that do not elicit an agonist response, may provide a therapeutic approach to the treatment of BPH. The true novelty of such a therapy is realized when prostate volume reduction is combined with the other desirable pharmacologic features of a SARM. Drug-related adverse events from 5-α-reductase inhibitors include erectile dysfunction, decrease libido, and decreased ejaculate volume [Andriole, G.; Bruchovsky, N.; Chung, L. W. K.; Matsumoto, A. M.; Rittmaster, R.; Roehrborn, C.; Russell, D.; Tindall, D. J. of Urology 2004, 172, 1399-1403]. A comparison study of the pharmacologic activity of a SARM to an antiandrogen, and a 5-α-reductase inhibitor in intact male rats was recently reported [Gao, W.; Kearbey, J. D.; Nair, V. A.; Chung, K.; Parlow, A. F.; Miller, D. D.; Dalton, J. T. Endocrinology, 2004, 145, 5420-5428].
Large studies investigating the use of high doses of testosterone as a means of male contraception have been and are currently being conducted [Gao, W.; Kearbey, J. D.; Nair, V. A.; Chung, K.; Parlow, A. F.; Miller, D. D.; Dalton, J. T. Endocrinology, 2004, 145, 5420-5428. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Lancet 1990, 336, 955-959]. Testosterone is a necessary component in the generation of sperm, but high doses actually inhibit formation of mature sperm. Sperm maturation relies on the secretion of LH and FSH. LH regulates testicular testosterone production by the Leydig cells and FSH stimulates Sertoli cells to provide nutrients to maturing sperm. T production is regulated through a feedback loop that involves the hypothalamus and pituitary glands. Testosterone signals the hypothalamus and pituitary to decrease production of gonadotropin releasing hormone which in turn lowers the secretion of LH and FSH. Supraphysiological levels of testosterone serve to inhibit LH and FSH secretion through the feedback loop [Wang, C.; Swerdloff, R. S. Am. J. Obstet. Gynecol. 2004, 190, S60-S68. Wang, C.; Swerdloff, R. S. Endocrine Updates 1999, 5, 303-319]. Lowered intratesticular levels of T and FSH decrease sperm production [Sharpe, R. M.; Donachie, K.; Cooper, I. J. Endo. 1988, 117, 19-26.].
A SARMs efficacy in male contraception is dependent on its ability to interfere with the HPT axis and also on its potential action on androgen receptors in the testes. A SARM from the aryl-propionamide class, C-6, exhibited significant gonadotropin suppression in castrated male rats [Chen, J.; Hwang, D. J.; Bohl, C. E.; Miller, D. D.; Dalton, J. T. J. Pharmacol. Exp. Ther. 2005, 312, 546-553]. While this study focused on the central mediation of spermatogenesis, further investigation of the direct effects of SARMs on androgen receptors in the Sertoli, Leydig, peritubular myoid, and vascular smooth muscle cells of the testis would increase our understanding of spermatogenic inhibitory mechanisms [Collins, L. L.; Lee, H.-J.; Chen, Y.-T.; Chang, M.; Hsu, H.-Y.; Yeh, S.; Chang, C. Cytogenet Genome Res. 2003, 103, 299-301].
Inhibition of spermatogenesis may not be a desired effect for individuals seeking the benefits of hormone replacement. In such cases, a desirable SARM profile would show no effects on the endogenous hormone levels and/or spermatogenesis, while still demonstrating marked anabolic effects in muscle and bone.
Hypoactive sexual desire disorder (HSDD) is prevalent in both men and women, though it is thought to be less common in men [Laumann E. O.; Paik A.; Rosen R. C. JAMA 1999, 281, 537-44]. There are multiple factors contributing to HSDD in men. The two major components are decreased libido and erectile dysfunction. Libido decreases with aging in men. Adequate plasma T levels are required for maintenance of normal libido. Testosterone deficiency decreases libido, but the threshold level of testosterone under which libido problems may occur is relatively low (290 ng/dL) [Buena, F.; Swerdloff, R. S.; Steiner, B. S.; Lutchmansingh, P.; Peterson, M. A.; Pandian M. R.; Galmarini, M.; Bhasin, S. Fertil. Steril. 1993, 59, 1118-23]. Low libido in aging men is associated with deficiency of bioavailable testosterone, whereas total testosterone showed no or only weak associations [Ansong, K. S.; Punwaney, R. B. J. Urol. 1999, 162, 719-721. Davidson, J. M.; Chen, J. J.; Crapo, L.; Gray, G. D.; Greenleaf, W. J.; Catania, J. A. J. Clin. Endo. Met. 1983, 57, 71-7]. Clinical studies investigating the effects of testosterone on male sexual dysfunction have been conducted [Morley, J. E.; Perry, H. M. 3rd Andropause: an Old Concept in New Clothing. Clinics in Geriatric Medicine 2003, 19, 507-28. Hajjar, R. R.; Kaiser, F. E.; Morley, J. E. J. Clin. Endo. Met. 1997, 82, 3793-3796. Morales, A.; Johnston, B.; Heaton, J. P. W.; Lundie, M. J. Urol. 1997, 157, 849-854]. Establishment of efficacy in these studies relies on the collection of soft data such as daily diary recordings and questionnaires regarding perceived libido. Testosterone replacement appears to have positive effects on libido, but the establishment of common clinically validated tools would serve to allow meaningful study interpretation and comparisons.
Incidence of erectile dysfunction increases with aging [Johannes, C. B.; Araujo, A. B.; Feldman, H. A.; Derby, C. A.; Kleinman, K. P.; McKinlay, J. B J. Urol. 2000, 163, 460-3]. The etiology of erectile dysfunction is usually multifactorial, and late-onset hypogonadism is a contributing factor in a minor percentage (8-15%) of cases [Kaiser F. E. Medical Clinics of North America 1999, 83, 1267-78]. There is an association between serum testosterone level and frequency, duration and degree of spontaneous nocturnal erections [Carani, C.; Bancroft, J.; Granata, A.; Del R10, G.; Marrama, P. Psychoneuroendocrinology 1992, 17, 647-54]. Although some studies found no relationship with testosterone levels in older men [Ahn, H. S.; Park, C. M.; Lee, S. W. BJU International 2002, 89, 526-530. Cunningham, G. R; Hirshkowitz, M; Korenman, S. G; Karacan, I. J. Clin. Endo. Met. 1990, 70, 792-7], other studies have reported reduced testosterone levels in patients with erectile dysfunction [Rhoden, E. L.; Teloken, C.; Sogari, P. R.; Souto, C. A. V. J. Urol. 2002, 167, 1745-1748].
Although no studies have been published to date, the use of SARMs for HSDD offers the potential to increase libido while not driving the stimulation of sexual accessory organs such as the prostate. T has been shown to aid in the treatment of erectile dysfunction. Because the threshold value for T required to enhance libido is so low, very low doses of a SARM may be employed in order to provide treatment.
The use of androgens to alleviate the physiological consequences of testosterone deficiency is well recognized in men. The concept of androgen deficiency in women, however, is not readily embraced. The clinical manifestations of T deficiency in women are decreased libido, lowered mood, a diminished sense of well-being, blunted motivation, and persistent fatigue. Clinically, the use of androgens in women has been shown to enhance sexual function, maintain BMD, and increase fat-free mass [Cameron, D. R.; Braunstein, G. D. Fert. Steril. 2004, 82, 273-289].
SARMs have the potential to offer the same benefits in women as androgen therapies without the unwanted side effects. Side effects from androgen therapy in women include: acne, hirsutism, and lowering of high-density lipoprotein (HDL) cholesterol levels. Limited preclinical studies exploring the use of SARMs for female indications have been published. [Hanada, K.; Furuya, K.; Yamamoto, N.; Nejishima, H.; Ichikawa, K.; Nakamura, T.; Miyakawa, M.; Amano, S.; Sumita, Y.; Oguro, N. Biol. Pharm. Bull. 2003, 26, 1563-1569. Gao, W.; Reiser, P. J.; Coss, C. C.; Phelps, M. A.; Kearbey, J. D.; Miller, D. D.; Dalton, J. T. Endocrinology 2005, 146(11), 4887-4897].
Thus, modulators of steroid hormone nuclear receptors that are highly specific for one receptor could offer greater benefit with less side effects in the treatment of both female and male related hormone responsive diseases.
USPTO Backgrounds
USPTO Backgrounds