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Selective androgen receptor modulators

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https://www.readbyqxmd.com/read/29137141/steroid-and-xenobiotic-receptor-signalling-in-apoptosis-and-autophagy-of-the-nervous-system
#1
REVIEW
Agnieszka Wnuk, Małgorzata Kajta
Apoptosis and autophagy are involved in neural development and in the response of the nervous system to a variety of insults. Apoptosis is responsible for cell elimination, whereas autophagy can eliminate the cells or keep them alive, even in conditions lacking trophic factors. Therefore, both processes may function synergistically or antagonistically. Steroid and xenobiotic receptors are regulators of apoptosis and autophagy; however, their actions in various pathologies are complex. In general, the estrogen (ER), progesterone (PR), and mineralocorticoid (MR) receptors mediate anti-apoptotic signalling, whereas the androgen (AR) and glucocorticoid (GR) receptors participate in pro-apoptotic pathways...
November 11, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29117944/small-molecule-sigma1-modulator-induces-autophagic-degradation-of-pd-l1
#2
Christina M Maher, Jeffrey D Thomas, Derick A Haas, Charles G Longen, Halley M Oyer, Jane Y Tong, Felix J Kim
Emerging evidence suggests that Sigma1 (SIGMAR1, also known as sigma-1 receptor) is a unique ligand-regulated integral membrane scaffolding protein that contributes to cellular protein and lipid homeostasis. Previously, we demonstrated that some small molecule modulators of Sigma1 alter endoplasmic reticulum (ER) associated protein homeostasis pathways in cancer cells, including the unfolded protein response and autophagy. Programmed death-ligand 1 (PD-L1) is a type 1 integral membrane glycoprotein that is co-translationally inserted into the ER and is processed and transported through the secretory pathway...
November 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29072838/correction-to-origins-of-regioselectivity-in-the-fischer-indole-synthesis-of-a-selective-androgen-receptor-modulator
#3
Elizabeth L Noey, Zhongyue Yang, Yanwei Li, Hannah Yu, Rachel N Richey, Jeremy M Merritt, Douglas P Kjell, K N Houk
No abstract text is available yet for this article.
October 26, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/29032351/testosterone-induced-modulation-of-peroxisomal-morphology-and-peroxisome-related-gene-expression-in-brown-trout-salmo-trutta-f-fario-primary-hepatocytes
#4
Célia Lopes, Fernanda Malhão, Cláudia Guimarães, Ivone Pinheiro, José F Gonçalves, L Filipe C Castro, Eduardo Rocha, Tânia V Madureira
Disruption of androgenic signaling has been linked to possible cross-modulation with other hormone-mediated pathways. Therefore, our objective was to explore effects caused by testosterone - T (1, 10 and 50μM) in peroxisomal signaling of brown trout hepatocytes. To study the underlying paths involved, several co-exposure conditions were tested, with flutamide - F (anti-androgen) and ICI 182,780 - ICI (anti-estrogen). Molecular and morphological approaches were both evaluated. Peroxisome proliferator-activated receptor alpha (PPARα), catalase and urate oxidase were the selected targets for gene expression analysis...
September 28, 2017: Aquatic Toxicology
https://www.readbyqxmd.com/read/28974548/selective-androgen-receptor-modulator-rad140-inhibits-the-growth-of-androgen-estrogen-receptor-positive-breast-cancer-models-with-a-distinct-mechanism-of-action
#5
Ziyang Yu, Suqin He, Dannie Wang, Hitisha K Patel, Chris P Miller, Jeff Brown, Gary Hattersley, Jamal C Saeh
PURPOSE: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer eliciting favorable response. The present study evaluates the activity and efficacy of the oral selective AR modulator (SARM) RAD140 in in vivo and in vitro models of AR/ER+ breast cancer. EXPERIMENTAL DESIGN: A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity...
October 3, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28938459/selective-glucocorticoid-receptor-antagonist-cort125281-activates-brown-adipose-tissue-and-alters-lipid-distribution-in-male-mice
#6
Jan Kroon, Lisa L Koorneef, Jose K van den Heuvel, Cristy R C Verzijl, Nienke M van de Velde, Isabel M Mol, Hetty C M Sips, Hazel Hunt, Patrick C N Rensen, Onno C Meijer
Glucocorticoids influence a wide range of metabolic processes in the human body and excessive glucocorticoid exposure is known to contribute to the development of metabolic disease. We evaluated the utility of the novel glucocorticoid receptor (GR) antagonist CORT125281 for its potential to overcome adiposity, glucose intolerance and dyslipidaemia, and compared this head-to-head with classic GR antagonist RU486 (mifepristone). We show that, while RU486 displays cross-reactivity to the progesterone and androgen receptor, CORT125281 selectively inhibits GR transcriptional activity...
September 18, 2017: Endocrinology
https://www.readbyqxmd.com/read/28931495/a-review-of-sarcopenia-enhancing-awareness-of-an-increasingly-prevalent-disease
#7
REVIEW
Eric Marty, Yi Liu, Andre Samuel, Omer Or, Joseph Lane
Sarcopenia is defined as an age associated decline in skeletal muscle mass. The pathophysiology of sarcopenia is multifactorial, with decreased caloric intake, muscle fiber denervation, intracellular oxidative stress, hormonal decline, and enhanced myostatin signaling all thought to contribute. Prevalence rates are as high as 29% and 33% in elderly community dwelling and long-term care populations, respectively, with advanced age, low body mass index, and low physical activity as significant risk factors. Sarcopenia shares many characteristics with other disease states typically associated with risk of fall and fracture, including osteoporosis, frailty, and obesity...
December 2017: Bone
https://www.readbyqxmd.com/read/28828592/drug-delivery-for-the-treatment-of-endometriosis-and-uterine-fibroids
#8
REVIEW
David R Friend
Endometriosis and uterine fibroids (also known as uterine leiomyomas) are serious medical conditions affecting large numbers of women worldwide. Many women are asymptomatic but those with symptoms require medical intervention to relieve chronic pain and dysmenorrhea and to address infertility. Drug delivery has played a role in reducing some of the symptoms associated with endometriosis and uterine fibroids. Use of drug delivery systems for both conditions can roughly be divided into two categories: (1) existing systems designed for other indications such as contraception for symptomatic relief and (2) development of novel systems aimed at addressing some of the underlying biochemical changes associated with endometriosis and uterine fibroids such as oxidative stress, angiogenesis, and matrix degradation...
December 2017: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/28717268/empiric-medical-therapy-with-hormonal-agents-for-idiopathic-male-infertility
#9
REVIEW
Nicholas N Tadros, Edmund S Sabanegh
INTRODUCTION: Infertility affects approximately 15% of all couples, and male factor contribute to up to 50% of cases. Unfortunately, the cause of male infertility is unknown in about 30% of these cases. Infertility of unknown origin is classified as idiopathic male infertility when abnormal semen parameters are present. Despite not having a definable cause, these men may respond to treatment. This review focuses on the use of empiric hormonal therapies for idiopathic male infertility...
July 2017: Indian Journal of Urology: IJU: Journal of the Urological Society of India
https://www.readbyqxmd.com/read/28696695/structure-based-approach-to-identify-5-4-hydroxyphenyl-pyrrole-2-carbonitrile-derivatives-as-potent-and-tissue-selective-androgen-receptor-modulators
#10
Ray Unwalla, James J Mousseau, Olugbeminiyi O Fadeyi, Chulho Choi, Kevin Parris, Baihua Hu, Thomas Kenney, Susan Chippari, Christopher McNally, Karthick Vishwanathan, Edward Kilbourne, Catherine Thompson, Sunil Nagpal, Jay Wrobel, Matthew Yudt, Carl A Morris, Dennis Powell, Adam M Gilbert, Eugene L Piatnitski Chekler
In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound 7, a potent AR (ARE EC50 = 0.34 nM) and selective (N/C interaction EC50 = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of 7, and further insights from modeling studies of ligand receptor interactions are also presented.
July 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28624515/development-of-selective-androgen-receptor-modulators-sarms
#11
REVIEW
Ramesh Narayanan, Christopher C Coss, James T Dalton
The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects...
June 15, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28621446/the-long-and-winding-road-for-selective-androgen-receptor-modulators
#12
James T Dalton
Numerous selective androgen receptor modulators (SARMs) with differing chemical structures and nearly ideal pharmacological and pharmacokinetic properties have been developed that are well tolerated and selectively increase lean body mass in humans. However, definitive demonstration of the linkage between lean body mass and physical function in a relevant, large patient population has remained elusive for a SARM. The clinical endpoints serving as their basis of approval have shifted with time and clinical indication and are likely to continue to do so as the field matures with additional safety and efficacy data pertaining to the relationship between lean body mass and physical function, regulatory decisions with SARMs and other agents, and yet unexplored clinical indications...
October 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28549707/interventions-for-treating-sarcopenia-a-systematic-review-and-meta-analysis-of-randomized-controlled-studies
#13
Yoshihiro Yoshimura, Hidetaka Wakabayashi, Minoru Yamada, Hunkyung Kim, Atsushi Harada, Hidenori Arai
BACKGROUND: Much interest has been focused on interventions for treating sarcopenia; however, the effects have gained little evidence. OBJECTIVE: To analyze the effectiveness of exercise, nutritional, drug, and combinational interventions for treating sarcopenia in older people. METHOD: We systematically searched MEDLINE via PubMed, the Cochrane Library of Cochrane Reviews and Cochrane Central Register of Controlled Trials, and Ichushi-Web for randomized controlled trials (RCTs) from January 2000 to December 2016...
June 1, 2017: Journal of the American Medical Directors Association
https://www.readbyqxmd.com/read/28504114/a-shortened-tamoxifen-induction-scheme-to-induce-creer-recombinase-without-side-effects-on-the-male-mouse-skeleton
#14
Ferran Jardí, Michaël R Laurent, Vanessa Dubois, Rougin Khalil, Ludo Deboel, Dieter Schollaert, Ludo Van Den Bosch, Brigitte Decallonne, Geert Carmeliet, Frank Claessens, Dirk Vanderschueren
The selective estrogen receptor modulator tamoxifen exerts estrogen agonistic or antagonistic actions on several tissues, including bone. The off-target effects of tamoxifen are one of the most widely recognized pitfalls of tamoxifen-inducible Cre recombinases (CreERs), potentially confounding the phenotypic findings. Still, the validation of tamoxifen induction schemes that minimize the side effects of the drug has not been addressed. Here, we compared the side effects on the skeleton and other androgen-responsive targets of a shortened tamoxifen regimen (2 doses of 190 mg/kg body weight by oral gavage) to a standard protocol (4 doses) and determined their efficiency in inducing CreER-mediated gene deletion...
May 11, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28497213/bone-pain-and-muscle-weakness-in-cancer-patients
#15
REVIEW
Daniel P Milgrom, Neha L Lad, Leonidas G Koniaris, Teresa A Zimmers
PURPOSE OF REVIEW: In this article, we will discuss the current understanding of bone pain and muscle weakness in cancer patients. We will describe the underlying physiology and mechanisms of cancer-induced bone pain (CIBP) and cancer-induced muscle wasting (CIMW), as well as current methods of diagnosis and treatment. We will discuss future therapies and research directions to help patients with these problems. RECENT FINDINGS: There are several pharmacologic therapies that are currently in preclinical and clinical testing that appear to be promising adjuncts to current CIBP and CIMW therapies...
April 2017: Current Osteoporosis Reports
https://www.readbyqxmd.com/read/28467062/origins-of-regioselectivity-in-the-fischer-indole-synthesis-of-a-selective-androgen-receptor-modulator
#16
Elizabeth L Noey, Zhongyue Yang, Yanwei Li, Hannah Yu, Rachel N Richey, Jeremy M Merritt, Douglas P Kjell, K N Houk
The selective androgen receptor modulator, (S)-(7-cyano-4-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)carbamic acid isopropyl ester, LY2452473, is a promising treatment of side effects of prostate cancer therapies. An acid-catalyzed Fischer indolization is a central step in its synthesis. The reaction leads to only one of the two possible indole regioisomers, along with minor decomposition products. Computations show that the formation of the observed indole is most favored energetically, while the potential pathway to the minor isomer leads instead to decomposition products...
May 17, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28454849/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
#17
Katsuji Aikawa, Moriteru Asano, Koji Ono, Noriyuki Habuka, Jason Yano, Keith Wilson, Hisashi Fujita, Hitoshi Kandori, Takahito Hara, Megumi Morimoto, Takashi Santou, Masuo Yamaoka, Masaharu Nakayama, Atsushi Hasuoka
We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring...
July 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28453658/androgen-receptor-agonists-increase-lean-mass-improve-cardiopulmonary-functions-and-extend-survival-in-preclinical-models-of-duchenne-muscular-dystrophy
#18
Suriyan Ponnusamy, Ryan D Sullivan, Dahui You, Nadeem Zafar, Chuan He Yang, Thirumagal Thiyagarajan, Daniel L Johnson, Maron L Barrett, Nikki J Koehler, Mayra Star, Erin J Stephenson, Dave Bridges, Stephania A Cormier, Lawrence M Pfeffer, Ramesh Narayanan
Duchenne muscular dystrophy (DMD) is a neuromuscular disease that predominantly affects boys as a result of mutation(s) in the dystrophin gene. DMD is characterized by musculoskeletal and cardiopulmonary complications, resulting in shorter life-span. Boys afflicted by DMD typically exhibit symptoms within 3-5 years of age and declining physical functions before attaining puberty. We hypothesized that rapidly deteriorating health of pre-pubertal boys with DMD could be due to diminished anabolic actions of androgens in muscle, and that intervention with an androgen receptor (AR) agonist will reverse musculoskeletal complications and extend survival...
July 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28449232/safety-pharmacokinetics-and-pharmacological-effects-of-the-selective-androgen-receptor-modulator-gsk2881078-in-healthy-men-and-postmenopausal-women
#19
Richard V Clark, Ann C Walker, Susan Andrews, Philip Turnbull, Jeffrey A Wald, Mindy H Magee
AIM: Selective androgen receptor modulators (SARMs) induce anabolic effects on muscle without the adverse effects of androgenic steroids. In this first-in-human study, we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of the SARM GSK2881078. METHODS: In Part A, healthy young men (n = 10) received a single dose of study drug (0 mg, 0.05 mg, 0.1 mg, 0.2 mg GSK2881078 or matching-placebo). In Part B, repeat-dose cohorts in men (n = 65) were 0...
October 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28440570/mass-spectrometric-characterization-of-the-selective-androgen-receptor-modulator-sarm-yk-11-for-doping-control-purposes
#20
Mario Thevis, Thomas Piper, Josef Dib, Andreas Lagojda, Dirk Kuehne, Lars Packschies, Hans Geyer, Wilhelm Schaenzer
RATIONALE: Selective androgen receptor modulators (SARMs) represent an emerging class of therapeutics targeting inter alia conditions referred to as cachexia and sarcopenia. Due to their anabolic properties, the use of SARMs is prohibited in sports as regulated by the World Anti-Doping Agency (WADA), and doping control laboratories test for these anabolic agents in blood and urine. In order to accomplish and maintain comprehensive test methods, the characterization of new drug candidates is critical for efficient sports drug testing...
April 25, 2017: Rapid Communications in Mass Spectrometry: RCM
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