Discovery of 6-<i>N,N</i>-Bis(2,2,2-trifluoroethyl)amino- 4-trifluoromethylquinolin-2(1<i>H</i>)-one as a Novel Selective Androgen Receptor Modulator

Oeveren, Arjan van; Motamedi, Mehrnouch; Mani, Neelakandha S.; Marschke, Keith B.; López, Francisco J.; Schrader, William T.; Negro-Vilar, and Andrés; Zhi, Lin

doi:10.1021/jm060792t

Cited by 71 publications

(49 citation statements)

References 28 publications

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“…The World Anti-Doping Agency's minimum required performance limit for an anabolic agent is 2 or 10 ng/mL in urine, depending on the compound [34]. Our method fulfills the requirements, especially in the case of the most potent [25,30] and, therefore, the most interesting Compound A, LGD-2226. There are probably two reasons for the excellent sensitivity of the method for Compound A: the compound is effectively ionized due to its high fluorine content, and there are only few background compounds originating from the urine matrix, while measuring the characteristic SRM ion pairs ( Figure 1 b and Supplementary Data).…”

Section: Analytical Performance Of Gc-appi-msmentioning

confidence: 91%

“…Analysis of SARMs in doping testing has an increasing importance since the number of drug candidates with anabolic effects is continuously growing [21]. SARMs based on the structures of for example aryl propionamide [22,23], quinoline [24], 2-quinolinone [25], and hydantoin [26] have been reported, and analytical methods for 2-quinolinone-derived SARMs by liquid chromatography-electrospray ionization-mass spectrome-try (LC-ESI-MS) [27] and gas chromatography-electron impact ionization-mass spectrometry (GC-EI-MS) [28] have been published. In this study, three nonsteroidal androgen receptor modulators derived from 2-quinolinone, including the drug candidate LGD-2226 [25,29,30], were analyzed in urine after enzymatic hydrolysis and derivatization by the combination of gas chromatography and microchip atmospheric pressure photoionization-tandem mass spectrometry (GC-APPI-MS/MS).…”

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confidence: 99%

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Analysis of selective androgen receptor modulators by gas chromatography-microchip atmospheric pressure photoionization-mass spectrometry

Luosujärvi

Haapala

Thevis

et al. 2010

J. Am. Soc. Mass Spectrom.

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A gas chromatography-microchip atmospheric pressure photoionization-mass spectrometric (GC-APPI-MS) method was developed and used for the analysis of three 2-quinolinone-derived selective androgen receptor modulators (SARMs). SARMs were analyzed from spiked urine samples, which were hydrolyzed and derivatized with N-methyl-N-(trimethylsilyl)trifluoroacetamide before analysis. Trimethylsilyl derivatives of SARMs formed both radical cations (M ϩ• ) and protonated molecules ([M ϩ H] ϩ ) in photoionization. Better signal-to-noise ratios (S/N) were obtained in MS/MS analysis using the M ϩ• ions as precursor ions than using the [M ϩ H] ϩ ions, and therefore the M ϩ• ions were selected for the precursor ions in selected reaction monitoring (SRM) analysis. Limits of detection (LODs) with the method ranged from 0.01 to 1 ng/mL, which correspond to instrumental LODs of 0.2-20 pg. Limits of quantitation ranged from 0.03 to 3 ng/mL. The mass spectrometric response to the analytes was linear (R Ն 0.995) from the LOQ concentration level up to 100 ng/mL concentration, and intra-day repeatabilities were 5%-9%. In addition to the GC-APPI-MS study, the proof-of-principle of gas chromatography-microchip atmospheric pressure chemical ionization-Orbitrap MS (GC-APCI-Orbitrap MS) was demonstrated. (J Am Soc Mass Spectrom 2010, 21, 310 -316)

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Section: Analytical Performance Of Gc-appi-msmentioning

confidence: 91%

mentioning

confidence: 99%

Analysis of selective androgen receptor modulators by gas chromatography-microchip atmospheric pressure photoionization-mass spectrometry

Luosujärvi

Haapala

Thevis

et al. 2010

J. Am. Soc. Mass Spectrom.

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“…Modeling results based on the 4-AR structure 17,9 indicates that the fluorine atoms on the 2,2,2-trifluoroethyl substitutent of 18h interacts with amino acid THR-877 which rationalizes the enhanced AR activity of the 2,2,2-trifluoroethyl substituent compared to the non-fluorinated side-chains (Figure 2). 18 The Aring also forms bifurcated hydrogen bonds with ARG-752 and GLN-711.…”

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confidence: 98%

“…A 2-week castrated mature rat assay was utilized to assess the AR mediated effect on organ weights. 9,10 The male sexual accessory organs, such as the ventral prostate (VP), are stimulated to grow and are maintained in size and function by the presence of endogenous androgens. This model is used to determine the androgen-dependent growth of the VP in mature castrated rats.…”

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confidence: 99%

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Potent, nonsteroidal selective androgen receptor modulators (SARMs) based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones

Higuchi

Thompson

Chen

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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A series of androgen receptor modulators based on 8H- [1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.The androgen receptor (AR) is a member of the intracellular receptor superfamily of liganddependent transcription factors. 1 The endogenous ligands for AR are the steroids testosterone (T) and dihydrotestosterone (DHT). When bound to AR, these ligands play important roles in sexual development and function, 2 and musculo-skeletal growth. 3 Steroidal androgen therapy is effective for the treatment of androgen insufficiency. However, the broader use of these androgens for additional treatments, such as osteoporosis or frailty, is limited by undesirable AR-mediated effects, such as prostatic hypertrophy and hirsutism. A selective androgen receptor modulator (SARM), with full anabolic activity but reduced impact on the undesirable effects could have a large role on endocrine therapies to treat muscle wasting and osteoporosis. 4 Early studies on modified androgens explored alkylation at C-17, as in fluoxymesterone (1 , Figure 1). 5 However, compounds from this general class are associated with potential liver toxicity. 2 Recent publications in the area of nonsteroidal androgens is indicative of the high level in discovering novel safe, effective anabolic agents (2, 3). [6][7][8] Our continued interest in SARMs is based on scaffolds derived from quinolin-2-ones (4 and 5). 9,10 During the course of our studies on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones (5a), we isolated as a minor byproduct of the Knorr quinolone reaction 11 regioisomer (6a, <5% yield, Scheme 1) which fortuitously possessed AR agonist activity in a transcriptional activation assay (78% agonist efficacy, 5 nM). Investigations into the scaffold led to a series of novel androgens derived from 8H-[1,4]oxazino[2,3-f]quinolin-8-ones (6). The lead compound from this series, 18h, demonstrated full efficacy in the maintenance of levator ani weight (LA) muscle, an anabolic endpoint in a castrated mature rat model.Our previous investigations of quinolinone scaffolds 4 and 5 revealed that the regions proximal to the tertiary amine group strongly affected AR activity. Consequently, we sought to probe

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Evolution of Selective Estrogen and Androgen Receptor Modulators: Status of Current Therapy and New Drug Development

Wurz

DeGregorio

2011

Pharmaceutical Sciences Encyclopedia

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Prior to the discovery of nonsteroidal selective estrogen and androgen receptor modulators (SERMs and SARMs), the only available treatment modalities for conditions such as menopausal symptoms and postmenopausal osteoporosis in women, and the symptoms associated with hypogonadism in men, were steroid based. As this chapter will discuss, recent clinical trial data have shown that the long‐term use of hormone replacement therapy in postmenopausal women is associated with an increased risk of breast cancer and may increase the risk of coronary heart disease and dementia, contrary to the results of previous observational studies. There are also concerns that androgen replacement therapy in hypogonadal men may pose a risk to prostate health, in addition to the difficulties inherent with the delivery of steroidal androgens. Thus, there is now great interest in developing nonsteroidal, orally bioavailable therapies, that is, SERMs and SARMs, that can provide the respective benefits of estrogens and androgens while minimizing their associated side effects.

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Discovery of 6-N,N-Bis(2,2,2-trifluoroethyl)amino- 4-trifluoromethylquinolin-2(1H)-one as a Novel Selective Androgen Receptor Modulator

Cited by 71 publications

References 28 publications

Analysis of selective androgen receptor modulators by gas chromatography-microchip atmospheric pressure photoionization-mass spectrometry

Analysis of selective androgen receptor modulators by gas chromatography-microchip atmospheric pressure photoionization-mass spectrometry

Potent, nonsteroidal selective androgen receptor modulators (SARMs) based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones

Evolution of Selective Estrogen and Androgen Receptor Modulators: Status of Current Therapy and New Drug Development

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