A novel selective androgen receptor modulator, NEP28, is efficacious in muscle and brain without serious side effects on prostate

Akita, Kazumasa; Harada, Koichiro; Ichihara, Junji; Takata, Naoko; Takahashi, Yoshio; Saito, Koichi

doi:10.1016/j.ejphar.2013.10.042

Cited by 39 publications

(29 citation statements)

References 31 publications

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“…SARMs have been widely investigated in preclinical animal models of muscle wasting, hypogonadism, osteoporosis, and other conditions (29)(30)(31)(32)(33)(34). Enobosarm is one of the SARMs developed for treating muscle-wasting diseases.…”

Section: Discussionmentioning

confidence: 99%

Prevention of body weight loss and sarcopenia by a novel selective androgen receptor modulator in cancer cachexia models

et al. 2017

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Abstract. Cancer cachexia is a syndrome that impairs the quality of life and overall survival of patients, and thus the effectiveness of anticancer agents. There are no effective therapies for cancer cachexia due to the complexity of the syndrome, and insufficient knowledge of its pathogenesis results in difficulty establishing appropriate animal models. Previously, promising results have been obtained in clinical trials using novel agents including the ghrelin receptor agonist anamorelin, and the selective androgen receptor modulator (SARM) enobosarm to treat cachexia in patients with cancer. The present study examined the pharmacological effects of SARM-2f, a novel non-steroidal small molecule SARM, in animal models. SARM-2f increased body and skeletal muscle weight without significantly increasing the weight of the seminal vesicles or prostates of the castrated male rats. In the mice with tumor necrosis factor α-induced cachexia, SARM-2f and TP restored body weight, carcass weight, and food consumption rate. In the C26 and G361 cancer cachexia animal models, body and carcass weight, lean body mass, and the weight of the levator ani muscle were increased by SARM-2f and TP treatments. Tissue selectivity of SARM-2f was also observed in these animal models. The results demonstrate the anabolic effects of SARM-2f in a cytokine-induced cachexia model and other cancer cachexia models, and suggest that SARM-2f may be a novel therapeutic option for cachexia in patients with cancer. IntroductionCancer cachexia is defined as a multifactorial disorder associated with an ongoing loss of skeletal muscle mass with or without loss of fat mass, which leads to a progressive functional impairment that cannot be fully reversed with conventional nutritional supplementation (1). The symptoms appear in up to 80% of patients with cancer and account for at least 20% of cancer-associated deaths (1,2). Cancer cachexia has been reported to be caused by nutritional deficiencies, metabolic disorders, and inflammatory disorders (3-6). Presently, however, there is no approved therapy for the treatment or prevention of cancer cachexia. Therefore, an effective therapy for cancer cachexia is an unmet medical need. There are several potential therapeutic approaches for cancer cachexia (7-10). Androgen is a steroid hormone with multiple physiological functions including promotion of growth hormone release, appetite stimulation, anabolic actions, stimulatory effects on the central nervous system (CNS), and regulation of energy homeostasis. Low plasma androgen levels are often observed in patients with terminal cancer (11,12). Therefore, androgen-based treatments might be a potential therapy for cancer cachexia. However, testosterone replacement therapy has unavoidable side effects such as myocardial infarction, heart failure, stroke, depression, and aggression (13,14).In a previous study, we reported the 4-(pyrrolidin-1-yl) benzonitrile derivative as a selective androgen receptor modulator (SARM)-1c (15). Unlike testosterone, SARM-1c exhibited an...

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Section: Discussionmentioning

confidence: 99%

Prevention of body weight loss and sarcopenia by a novel selective androgen receptor modulator in cancer cachexia models

et al. 2017

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“…Other than the above clinical candidates, phase I clinical studies of BMS-564929 (Bristol-Myers Squibb) 21,30,31) , GLPG0492 (Galapagos) 32,33) , LY2452473 (Eli Lilly) 34) , GSK971086 (GlaxoSmithKline) 28) , and S-101479 (Kaken Pharmaceuticals) 35,36) have been implemented. In addition, a pre-clinical study of castrated rats demonstrated that NEP28 (Sumitomo Chemical) strongly enhanced the development of muscle, and restored muscle weight to the eugonadal level without excessive undesired pharmacological effects on the prostate 37) .…”

Section: Mk-0773mentioning

confidence: 99%

Possibility of small-molecule-based pharmacotherapy for sarcopenia

Watanabe

Miyagoe-Suzuki

2015

JPFSM

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Muscle mass and strength decline with age. When severe, the loss is called sarcopenia. Sarcopenia is drawing attention worldwide, especially in highly aged societies, as a disease that should be treated. At present, we have limited tools to combat sarcopenia (e.g. resistance training and nutritional intervention), but accumulating knowledge of the molecular and cellular mechanisms of sarcopenia is accelerating the development of pharmacological therapies for sarcopenia. Because sarcopenia is a complicated pathological condition caused and modified by many aging-related factors, such as inactivity, loss of motor neurons, poor nutrition, decline of anabolic hormones, chronic inflammation, oxidative stress, impaired stem cell function, and comorbidity, the proposed target molecules or pathways for pharmacological intervention are diverse. Here we review recent progress in drug development with emphasis on small-molecule compound-based therapies and review the literature to identify new therapeutic targets to prevent, delay, or reverse sarcopenia.

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“…However, it remains to be shown which of these metabolites de facto occur(s) in humans and which might offer the longest window of opportunity to detect the misuse of ACP‐105 (Figure , 3 ). Comparably little is known about the ADME properties of the recently reported SARM NEP28 (Figure , 4 ) . Its anabolic efficiency equivalence was demonstrated in comparison studies with dihydrotestosterone (DHT) and methyltestosterone, suggesting its utility in the treatment of sarcopenia as well as osteoporosis and, thus, the necessity to include it in doping control analyses.…”

Section: Anabolic Agentsmentioning

confidence: 99%

“…Comparably little is known about the ADME properties of the recently reported SARM NEP28 (Figure 1, 4). [76] Its anabolic efficiency equivalence was demonstrated in comparison studies with dihydrotestosterone (DHT) and methyltestosterone, suggesting its utility in the treatment of sarcopenia as well as osteoporosis and, thus, the necessity to include it in doping control analyses. Furthermore, the potential benefit concerning therapeutic means of NEP28 treatment for Alzheimer's disease was suggested due to an increase in neprilysin activity and consequently, degradation of amyloid beta peptide.…”

Section: Confirmatory Testing Procedures -Irms: Complementary Informamentioning

confidence: 99%

Annual banned‐substance review: analytical approaches in human sports drug testing

Thevis

Kuuranne

Geyer

et al. 2014

Drug Testing and Analysis

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Within the mosaic display of international anti-doping efforts, analytical strategies based on up-to-date instrumentation as well as most recent information about physiology, pharmacology, metabolism, etc., of prohibited substances and methods of doping are indispensable. The continuous emergence of new chemical entities and the identification of arguably beneficial effects of established or even obsolete drugs on endurance, strength, and regeneration, necessitate frequent and adequate adaptations of sports drug testing procedures. These largely rely on exploiting new technologies, extending the substance coverage of existing test protocols, and generating new insights into metabolism, distribution, and elimination of compounds prohibited by the World Anti-Doping Agency (WADA). In reference of the content of the 2014 Prohibited List, literature concerning human sports drug testing that was published between October 2013 and September 2014 is summarized and reviewed in this annual banned-substance review, with particular emphasis on analytical approaches and their contribution to enhanced doping controls.

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A novel selective androgen receptor modulator, NEP28, is efficacious in muscle and brain without serious side effects on prostate

Cited by 39 publications

References 31 publications

Prevention of body weight loss and sarcopenia by a novel selective androgen receptor modulator in cancer cachexia models

Prevention of body weight loss and sarcopenia by a novel selective androgen receptor modulator in cancer cachexia models

Possibility of small-molecule-based pharmacotherapy for sarcopenia

Annual banned‐substance review: analytical approaches in human sports drug testing

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