Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part I

Aikawa, Katsuji; Miyawaki, Toshio; Hitaka, Takenori; Imai, Yumi; Hara, Takahito; Miyazaki, Junichi; Yamaoka, Masuo; Kusaka, Masami; Kanzaki, Naoyuki; Tasaka, Akihiro; Shiraishi, Masayuki; Yamamoto, Satoshi

doi:10.1016/j.bmc.2015.03.032

Cited by 19 publications

(13 citation statements)

References 13 publications

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“…A double-blind, placebo-controlled, interventional study investigating this is currently in progress (NCT00878995). The major concern associated with testosterone use is the unavoidable side effects such as cardiovascular disorders (14,15), which may be partly attributable to estrogen derived from testosterone (13,28). However, SARM-2f is not a substrate of aromatase, which is the enzyme that converts testosterone to estradiol.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike testosterone, SARM-1c exhibited anabolic effects on the levator ani muscles without excessively increasing prostate weight in rat Hershberger assays (15). We further improved the pharmacokinetic (PK) profile by modifying the structure and identified 4-[(2S,S) -2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl) benzonitrile (SARM-2f) as a novel SARM (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…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 anabolic effects on the levator ani muscles without excessively increasing prostate weight in rat Hershberger assays (15).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

confidence: 99%

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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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“…[2] SARMs action is directed at AR of muscles (growth and strength) and bones (development). [1,[12][13][14] While SARMs are on the World Anti-Doping Agency (WADA) list of prohibited substances, [4] cases of human doping and misuse by athletes are reported from time to time. [6,10,11] Several chemical structures have been developed as non-steroidal SARMs: quinolone analogues, hydantoin analogues, tetrahidro-quinolone analogues, and aryl-propionamide analogues [1,6] SARMs belonging to the aryl-propionamide group have been the first ones to show an interesting agonistic activity with a tissue-selective action in the steroidal signalling pathway.…”

Section: Introductionmentioning

confidence: 99%

“…[6,10,11] Several chemical structures have been developed as non-steroidal SARMs: quinolone analogues, hydantoin analogues, tetrahidro-quinolone analogues, and aryl-propionamide analogues [1,6] SARMs belonging to the aryl-propionamide group have been the first ones to show an interesting agonistic activity with a tissue-selective action in the steroidal signalling pathway. [1,[12][13][14] While SARMs are on the World Anti-Doping Agency (WADA) list of prohibited substances, [4] cases of human doping and misuse by athletes are reported from time to time. [15][16][17] SARMs may also exhibit a high potential for misuse in animal husbandry as growth promoters to increase weight gain, improve carcass quality, and reduce production costs.…”

Section: Introductionmentioning

confidence: 99%

Selective androgen receptor modulators: comparative excretion study of bicalutamide in bovine urine and faeces

Rojas

Cesbron

Penot

et al. 2016

Drug Testing and Analysis

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Besides their development for therapeutic purposes, non-steroidal selective androgen receptor modulators (non-steroidal SARMs) are also known to impact growth-associated pathways as ligands of androgenic receptors (AR). They present a potential for abuse in sports and food-producing animals as an interesting alternative to anabolic androgenic steroids (AAS). These compounds are easily available and could therefore be (mis)used in livestock production as growth promoters. To prevent such practices, dedicated analytical strategies should be developed for specific and sensitive detection of these compounds in biological matrices. The present study focused on Bicalutamide, a non-steroidal SARM used in human treatment of non-metastatic prostate cancer because of its anti-androgenic activity exhibiting no anti-anabolic effects. To select the most appropriate matrix to be used for control purposes, different animal matrices (urine and faeces) have been investigated and SARM metabolism studied to highlight relevant metabolites of such treatments and establish associated detection time windows. The aim of this work was thus to compare the urinary and faecal eliminations of bicalutamide in a calf, and investigate phase I and II metabolites. The results in both matrices showed that bicalutamide was very rapidly and mainly excreted under its free form. The concentration levels were observed as higher in faeces (ppm) than urine (ppb); although both matrices were assessed as suitable for residue control. The metabolites found were consistent with hydroxylation (phase I reaction) combined or not with glucuronidation and sulfation (phase II reactions). Copyright © 2016 John Wiley & Sons, Ltd.

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1,3‐Dipolar Cycloaddition of 3‐Chromonyl‐Substituted Glycine Imino Esters with Arylidenes and in situ Diastereodivergent via Retrocycloaddition

Foad

Elboray

Dardeer

et al. 2023

Chemistry An Asian Journal

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1,3-Dipolar cycloaddition through in situ generation of azomethine ylide provides a straightforward and critically important sustainable approach for access to diverse pyrrolidine chemical space. Herein, we developed a metal-free AcOH-activated 1,3-dipolar cycloaddition protocol that permits the synthesis of uncommon pyrrolidine cycloadducts with excellent diastereoselectivity. The challenging substrates of 3-formylchromone, glycine ester.HCl and arylidene dipolarophile were reacted in the presence of AcONa, which played a dual role as a base and AcOH source, to deliver firstly endocycloadduct. Under prolonged reaction time at room temperature or heating; the endo-adduct underwent diastereodiver-gent via a sequence of retro-cycloaddition, stereomutation of the generated syn-dipole into anti-dipole and recycloaddition; to furnish the scarcely known exo'-cycloadduct with high diastereodivergency. The reaction worked well with a broad range of substrates and the stereochemistry of the obtained cycloadducts was determined without ambiguity using NMR-and X-ray analysis. Experimental and theoretical DFT calculation studies were performed to support the proposed reaction mechanism and elucidate the key role of AcOH in the process which seems more beneficial than other transition metal-catalyzed processes.

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Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part I

Cited by 19 publications

References 13 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

Selective androgen receptor modulators: comparative excretion study of bicalutamide in bovine urine and faeces

1,3‐Dipolar Cycloaddition of 3‐Chromonyl‐Substituted Glycine Imino Esters with Arylidenes and in situ Diastereodivergent via Retrocycloaddition

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