Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs) Part III: Discovery of 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2f as a clinical candidate

Aikawa, Katsuji; Asano, Masaharu; Ono, Koji; Habuka, Noriyuki; Yano, Jason; Wilson, Keith; Fujita, Hisashi; Kandori, Hitoshi; Hara, Takahito; Morimoto, Megumi; Santou, Takashi; Yamaoka, Masuo; Nakayama, Masaharu; Hasuoka, Atsushi

doi:10.1016/j.bmc.2017.04.018

Cited by 35 publications

(38 citation statements)

References 39 publications

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“…We previously demonstrated that at a dose of 0.5 mg/kg QD (p.o. ), SARM-2f enhanced the sexual behavior of castrated rats (22). In the present study, SARM-2f increased the food intake of mice with TNFα-induced cachexia.…”

Section: Discussionmentioning

confidence: 53%

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: 53%

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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“…The pharmacokinetic parameters were similar between rats and monkeys. The AUC 0‐24h values after a single oral administration of SARM‐2f at 1 mg/kg are 809.4 ng∙h/mL and 557.8 ng∙h/mL, respectively, and MRT (Mean Residence Time) was 3.06 and 5.21 hours, respectively, for rats and monkeys . The Vdss value after intravenous administration at 0.1 mg/kg was 2167 mL/kg and 1409 mL/kg for rats and monkeys, respectively .…”

Section: Discussionmentioning

confidence: 98%

“…We previously reported that SARM‐2f increased skeletal muscle weight with a much lesser effect on prostate weight . The mechanisms for tissue selectivity of SARM includes two factors: recruitment of specific cofactors to AR and a tissue‐specific cofactor expression profile .…”

Section: Discussionmentioning

confidence: 99%

“…Selective androgen receptor modulator (SARM) compounds, such as ostarine, significantly increased body weight, muscle mass, and muscle strength in preclinical rodent studies, and increased muscle mass in clinical trials . Our non‐steroidal small molecule, SARM compound, SARM‐2f (4′‐[(2S,3S)‐2‐Ethyl‐3‐hydroxy‐5‐oxopyrrolidin‐1‐yl]‐2′‐(trifluoromethyl) benzonitrile), also increases muscle weight and stimulates motor activity, food intake, and sexual behavior in rodent models . Currently, there are only a few reports showing the pharmacological effect of SARM compounds in monkeys: effects on blood high‐density lipoprotein cholesterol (HDL‐c) and overall gene expression profiles in the muscle .…”

Section: Introductionmentioning

confidence: 99%

“…14 Our non-steroidal small molecule, SARM compound, SARM-2f (4′-[(2S,3S)-2-Ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2′-(trifluoromethyl) benzonitrile), also increases muscle weight and stimulates motor activity, food intake, and sexual behavior in rodent models. [15][16][17] Currently, there are only a few reports showing the pharmacological effect of SARM compounds in monkeys: effects on blood high-density lipoprotein cholesterol (HDL-c) 18 and overall gene expression profiles in the muscle. 19 In this study, we investigated the pharmacological effects of SARM-2f in cynomolgus monkeys in vitro and in vivo.…”

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A selective androgen receptor modulator SARM‐2f activates androgen receptor, increases lean body mass, and suppresses blood lipid levels in cynomolgus monkeys

Morimoto

Yamaoka

Hara

2020

Pharmacology Res & Perspec

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SARM‐2f a selective androgen receptor (AR) modulator, increases skeletal muscle mass and locomotor activity in rats. This study aimed to clarify its pharmacological effects in monkeys. In reporter assays, the EC50 values of SARM‐2f for rat, monkey, and human AR were 2.5, 3, and 3.6 nmol/L, respectively; those of testosterone were 12, 3.2, and 11 nmol/L, respectively. A single oral administration (10 mg/kg SARM‐2f) produced a maximal plasma concentration of 3011 ng/mL, with an area under the 24 hours concentration‐time curve of 8152 ng·h/mL in monkeys. Body weight (BW), lean body mass (LBM), and plasma levels of total cholesterol, triglyceride, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, lipoprotein (a), alanine aminotransferase, and asparagine aminotransferase were measured after 4 weeks of treatment with SARM‐2f (1, 3, and 10 mg/kg/day, QD, p.o.) or testosterone enanthate (TE; 2 mg/kg/2 weeks, s.c.) in monkeys. BW and LBM were significantly increased by 12% each by SARM‐2f at 10 mg/kg, and by 5% and 8%, respectively, by TE, but these effects were not statistically significant. Plasma levels of all lipids were either decreased or showed a tendency to be decreased by SARM‐2f. TE decreased the triglyceride level and increased the low‐density lipoprotein cholesterol level. Liver marker levels were not changed by either SARM‐2f or TE. Our data demonstrated that SARM‐2f exerted anabolic effects and produced a lipid profile that differed from that produced by testosterone in monkeys, suggesting that SARM‐2f might be useful for diseases such as sarcopenia.

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Modulation of the Androgen Receptor Axis

Mohler

Dalton

2021

Burger's Medicinal Chemistry and Drug Discovery

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The androgen receptor (AR) mediates the endocrine functions of endogenous androgens like testosterone and exerts pleiotropic androgenic (male phenotype development, sexual function) and anabolic (growth and maintenance of musculoskeletal system) effects across most tissues. The AR‐axis, i.e. AR and its downstream effects, is extensively targeted to stimulate anabolism or treat prostatic diseases. Tissue‐selective, direct‐acting synthetic AR agonists are limited in scope by their inadequate separation of anabolic from untoward androgenic or virilizing effects and include FDA approved steroidal androgens (anabolic‐androgenic steroids) and investigational nonsteroidal selective AR modulators (SARMs). Gaining in popularity is testosterone replacement therapy in hypogonadal men. Antagonism of the AR‐axis is common in aging males with androgen‐dependent prostate hyperproliferation [prostate cancer or benign prostatic hyperplasia (BPH)]. Androgen ablation (indirect antagonism) and direct AR antagonism have been the mainstays of prostate cancer therapies for many decades including recent approvals. Indirect antagonists of the AR‐axis include gonadotropin‐releasing hormone agonists or antagonists (androgen‐deprivation therapy), which achieve systemic androgen and estrogen ablation for prostate or breast cancers as a monotherapy or sometimes in combination with steroidogenic enzyme (lyase) inhibitors. DHT‐dependent diseases are treated with 5α‐reductase to block intracrine production of DHT for male pattern baldness and BPH; whereas aromatase inhibitors block androgen metabolism to estrogen in breast cancer. Direct AR antagonists (antiandrogens) with improved potency and anti‐androgenic scope continue to be approved for prostate cancer. Research into innovative ways to directly or indirectly modulate the AR‐axis remains robust, suggesting new therapies will likely be introduced regularly for the foreseeable future.

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Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs) Part III: Discovery of 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2f as a clinical candidate

Cited by 35 publications

References 39 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

A selective androgen receptor modulator SARM‐2f activates androgen receptor, increases lean body mass, and suppresses blood lipid levels in cynomolgus monkeys

Modulation of the Androgen Receptor Axis

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