Nonsteroidal Tissue‐Selective Androgen Receptor Modulators

Mohler, Michael L.; Bohl, Casey E.; Narayanan, Ramesh; He, Yu‐Ying; Hwang, Dong-Jin; Dalton, James T.; Miller, Duane D.

doi:10.1002/9783527623297.ch8

Cited by 10 publications

(13 citation statements)

References 172 publications

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“…Since even before our discovery of diaryl nonsteroidal androgens in 1998, − we have designed and developed many variations of AR agonist and AR antagonist propanamides with a recent focus on SARDs (or AR degraders; where selectivity refers to degrading only the AR protein) such as 3 and 7 (Figures and ) . SAR studies of the propanamides demonstrated that the linkage to the B-ring plays a key role in determining the agonistic versus antagonistic activities (Figure ), which can be fine-tuned via B-ring substitution. − ,− Many ethers (and thioethers in vitro) are agonists, whereas most other linkages are partial to full antagonist. For example, enobosarm (ostarine, MK-2866, GTx-024, S-22, 2 in Figure ) showed strong in vivo ,− tissue-selective AR modulation (SARM) activity.…”

Section: Resultsmentioning

confidence: 99%

New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity

Hwang

Ponnusamy

et al. 2018

J. Med. Chem.

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In our effort to find small-molecule treatments of advanced prostate cancers (PCs), a novel series of indolyl and indolinyl propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced submicromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). II and III maintained potency against enzalutamide-resistant (Enz-R) mutant ARs and PC cells and were efficacious in Enz-R xenografts, suggesting their potential to treat advanced PCs. Design, synthesis, and biological activity of novel SARDs that could potentially be used for the treatment of a wide spectrum of PCs including castration-resistant, Enz-R, and/or AR SV-dependent advanced PCs that are often untreatable with known hormone therapies are discussed.

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Section: Resultsmentioning

confidence: 99%

New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity

Hwang

Ponnusamy

et al. 2018

J. Med. Chem.

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“…Currently, selected SARMs are undergoing clinical evaluation concerning the treatment of muscle wasting in cancer and sarcopenia. Other conditions such as age‐related functional decline and geriatric frailty have been also considered potential targets for SARM therapy …”

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confidence: 99%

“…Other conditions such as age-related functional decline and geriatric frailty have been also considered potential targets for SARM therapy. [2,[4][5][6][7][8] Since January 2008, the entire class of androgen receptor modulators has been prohibited in sports according to the regulations of the World Anti-Doping Agency (WADA). [9] Various studies have been conducted to elucidate the metabolic pathways of primarily arylpropionamide-derived SARMs and to allow the development of detection assays for these emerging drugs.…”

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confidence: 99%

Mass spectrometric characterization of urinary metabolites of the selective androgen receptor modulator S‐22 to identify potential targets for routine doping controls

Thevis

Thomas

Möller

et al. 2011

Rapid Comm Mass Spectrometry

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Drugs that promote anabolic processes with limited undesirable effects are of considerable therapeutic interest; some notable examples include those for the treatment of cancer cachexia and muscle-wasting diseases. Anabolic properties are not only therapeutically beneficial to critically ill and debilitated patients, but are also desirable to athletes seeking artificial enhancements in endurance, strength and accelerated recovery. The use of anabolic agents in the clinical setting is being reconsidered with the emergence of a new class of drugs referred to as SARMs (selective androgen receptor modulators). SARMs have the potential to complement or even replace anabolic androgenic steroidal use with the benefit of a reduction of the undesirable side effects associated with steroid administration alone. Arylpropionamide-based SARMs such as andarine (S-4) and S-22 have shown promising therapeutic properties and have attracted the interest of elite and amateur athletes despite the absence of clinical approval, and evidence for trafficking and misuse in sport has been obtained by doping control authorities. In this communication, the elucidation of urinary metabolites of the SARM drug candidate S-22 is compared with earlier in vitro metabolism studies. Following oral administration of illicit S-22, urine samples were collected after 62 and 135 h and analyzed for the active drug and its major metabolic products. Liquid chromatography interfaced with high-resolution/high-accuracy (tandem) mass spectrometry was used to identify and/or confirm the predicted target analytes for sports drug testing purposes. S-22 was detected in both specimens accompanied by its glucuronic acid conjugate. This was the B-ring hydroxylated derivative of S-22 plus the corresponding glucuronide (with the phase-II metabolites being the more abundant analytes). In addition, the samples collected 62 h post-administration also contained the phase-I metabolite hydroxylated at the methyl residue (C-20) and the B-ring depleted degradation product ('dephenylated' S-22) together with the corresponding carboxy analog that was previously reported for canine metabolism. The obtained data supports future efforts to effectively screen for and confirm the misuse of the non-approved S-22 drug candidate in doping controls.

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“…2,3 The therapeutic potential of androgen signaling is well-appreciated in the medicinal chemistry community, and for quite some time, chemists have sought compounds that selectively stimulate muscle and bone growth while minimizing the proliferative and/or hypertrophic effects on sex tissues such as the prostate in males and clitoris in females. 4,5 Such compounds have been termed selective androgen receptor modulators or SARMs. In this regard, the prototypical and endogenous androgen, testosterone, is considered to be a logical benchmark comparator.…”

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confidence: 99%

Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140

Miller

Shomali

Lyttle

et al. 2010

ACS Med. Chem. Lett.

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This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.KEYWORDS Androgen, SARM, cachexia, oxadiazole, Herschberger assay, primate T he androgen receptor (AR) is a member of the steroid hormone nuclear receptor superfamily that includes estrogen, progestin, glucocorticoid and mineralocorticoid receptors. 1 The binding of the prototypical, endogeneously produced androgen testosterone (1) and the important active metabolite dihydrotestosterone (2) to AR initiates a remarkably diverse array of biological activities that can vary according to a subject's sex, age and hormonal status. The activity of AR is critical to normal human sexual development and function, but beyond this signature role, AR activation also has important effects on diverse targets such as bone, liver, muscle and the central nervous system. 2,3 The therapeutic potential of androgen signaling is well-appreciated in the medicinal chemistry community, and for quite some time, chemists have sought compounds that selectively stimulate muscle and bone growth while minimizing the proliferative and/or hypertrophic effects on sex tissues such as the prostate in males and clitoris in females. 4,5 Such compounds have been termed selective androgen receptor modulators or SARMs. In this regard, the prototypical and endogenous androgen, testosterone, is considered to be a logical benchmark comparator. Compound 3 is the GTx SARM S-22 and compound 4 is the BMS SARM 562929, both of which have been reported in the literature as being orally active compounds with selectivity for muscle over prostate relative to testosterone in various preclinical models. 6,7 The possibility of obtaining compounds having tissueselective activities that are different from that of the endogenous benchmark testosterone might derive from the fact that typical AR receptor activation, which is initiated by the binding of a molecule with affinity for the AR to the AR ligand binding domain, is then followed by a rather remarkable, coordinated series of interactions: These may include a change in receptor topology, dissociation of heat shock proteins, receptor dimerization, receptor phosphorylation, rapid-signaling events, translocation to the nucleus (AR), association with many different coregulatory proteins to form a transcriptional complex that results in the activation or suppression of RNA synthesis from AR-modulated genes, and finally receptor degradation. 8 Since each receptor-ligand complex topology is unique to that ligand structure, one can appreciate that the interaction of any particular ligand-receptor complex with coregulatory proteins is likely to be unique to that ligand as well. Furthermore, because the expression level of AR, the constellation and expression level of coregulatory proteins, and the patterns of post-transcriptional regulatory events differ in each type of androgen...

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Nonsteroidal Tissue‐Selective Androgen Receptor Modulators

Cited by 10 publications

References 172 publications

New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity

New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity

Mass spectrometric characterization of urinary metabolites of the selective androgen receptor modulator S‐22 to identify potential targets for routine doping controls

Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140

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