LGD-3303
目录号 : GC32403
LGD-3303是一种选择性雄激素受体调节剂(SARM)。
Cas No.:917891-35-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Kinase experiment: |
In vitro binding is determined using recombinant baculovirus expressed human androgen receptor (hAR), human glucocorticoid receptor (hGR), human mineralocorticoid receptor (hMR), or human progesterone receptor (hPR). Tritium-labeled reference ligand is used with varying concentrations of LGD-3303 as a competing ligand. Inhibition constant (Ki) values are calculated by application of the Cheng-Prusoff equation. Reporter assays are performed. Briefly, CV1 cells are cultured in DMEM supplemented with 10% charcoal resin-stripped fetal bovine serum (FBS), and seeded 48 h before transfection in 96-well microtiter plates. Cells are transiently transfected using a nonliposomal formulation, the FuGENE 6 transfection reagent, with luciferase reporter plasmids MMTV-LUC or MTV-ERE5-LUC, a β-galactosidase (β-Gal) expression plasmid coding for the constitutive expression of Escherichia coli β-galactosidase, and hAR, hGR, hMR, hPR, or human estrogen receptor α (pRShERα) expression plasmids. Cells are treated with varying concentrations of LGD-3303 or reference compound for 40 h. The normalized luciferase response is calculated as relative luciferase units/(β-gal O.D415/β-Gal incubation time in minutes). The effective concentration that produces 50% of the maximum response (EC50) is determined, and agonist efficacy is calculated as a percent of normalized luciferase response relative to the maximum response by the reference agonist (i.e., DHT for hAR, dexamethasone for hGR, aldosterone for hMR, progesterone for hPR-B, or 17β-estradiol for hERα)[1]. |
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Animal experiment: |
Rats[2]Male Sprague-Dawley rats (7-8 weeks old, 200 g) are used. Rats are sorted by weight, assigned to experimental groups (n=5/group), and surgery is performed. Experimental groups consist of LGD-3303 (doses ranged from 0.1-300 mg/kg/day) or vehicle. LGD-3303 is administered by once daily oral gavage in a volume of 4 mL/kg. On the 14th day, blood is collected into lithium heparin tubes by jugular puncture at 0, 0.5, 1, 2, 4, and 6 h postdosing from the animals in the high-dose groups. Blood is centrifuged, and plasma is stored at -20°C for pharmacokinetic analysis. On the 15th day, rats are killed by decapitation, and trunk blood is collected, allowed to clot in serum separator tubes, and centrifuged, and serum is stored at -80°C for future analysis of serum luteinizing hormone (LH) levels. The wet weights of the ventral prostate, levator ani muscle, and preputial gland are measured at necropsy[2]. |
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References: [1]. Vajda EG, et al. Combination treatment with a selective androgen receptor modulator q(SARM) and a bisphosphonate has additive effects in osteopenic female rats. J Bone Miner Res. 2009 Feb;24(2):231-40. |
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LGD-3303 is a selective androgen receptor modulator (SARM).
LGD-3303 is a nonsteroidal, nonaromatizable androgen receptor ligand that binds to the androgen receptor with high affinity in a radiolabeled to competitive binding assay (Ki=0.9 nM). LGD-3303 binds to the mineralocorticoid, glucocorticoid, and progesterone receptors with greatly reduces affinity in comparison with the androgen receptor (Ki=1261, 581, and 136 nM, respectively). LGD-3303 potently activates transcription through the androgen receptor (EC50=3.6 nM) and has 134% efficacy relative to the steroidal androgen Dihydrotestosterone (DHT)[1].
LGD-3303 completely inhibits the loss of muscle weight with an oral dose of 1 mg/kg/day. At higher doses, LGD-3303 significantly increases levator ani muscle weight above eugonadal levels. In contrast, LGD-3303 has greatly reduced potency and efficacy on the other measured endpoints. LGD-3303 does not maintain eugonadal levels of serum LH at doses less than 10 mg/kg/day. LGD-3303 maintains eugonadal prostate weight only at doses of 100 mg/kg/day or greater and never fully returns the mean preputial gland weight to eugonadal levels at any tested dos. In no case does LGD-3303 restore LH, prostate, or preputial gland weights to supraphysiological levels significantly exceeding sham-operated controls. The ventral prostate, in particular, demonstrates a greatly reduced response to LGD-3303. At the muscle normalizing dose (1 mg/kg/day), ventral prostate weight is not significantly increased above the level of ORDX control rats (20% efficacy relative to intact rats). At the highest doses tested, ventral prostate never significantly exceeds eugonadal levels and reaches an apparent plateau with minimal increase in prostate weight as dosing escalated from 30 to 300 mg/kg/day. To investigate this apparent plateau in pharmacological activity, plasma concentrations of LGD-3303 are analyzed from the highest dose groups. Exposure to LGD-3303 (AUC0-6) monotonically increases with dose from 10 to 300 mg/kg/day[2].
[1]. Vajda EG, et al. Combination treatment with a selective androgen receptor modulator q(SARM) and a bisphosphonate has additive effects in osteopenic female rats. J Bone Miner Res. 2009 Feb;24(2):231-40. [2]. Vajda EG, et al. Pharmacokinetics and pharmacodynamics of LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one], an orally available nonsteroidal-selective androgen receptor modulator. J Pharmacol Exp Ther. 2009 Feb;328(2):663-70.
| Cas No. | 917891-35-1 | SDF | |
| Canonical SMILES | O=C1NC2=C(C3=C(N(CC(F)(F)F)C(CC)=C3C)C=C2)C(Cl)=C1 | ||
| 分子式 | C16H14ClF3N2O | 分子量 | 342.74 |
| 溶解度 | DMSO : 6 mg/mL (17.51 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.9177 mL | 14.5883 mL | 29.1766 mL |
| 5 mM | 0.5835 mL | 2.9177 mL | 5.8353 mL |
| 10 mM | 0.2918 mL | 1.4588 mL | 2.9177 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Pharmacokinetics and pharmacodynamics of LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one], an orally available nonsteroidal-selective androgen receptor modulator
J Pharmacol Exp Ther 2009 Feb;328(2):663-70.PMID:19017848DOI:10.1124/jpet.108.146811.
Selective androgen receptor modulators (SARMs) are a new class of molecules in development to treat a variety of diseases. SARMs maintain the beneficial effects of androgens, including increased muscle mass and bone density, while having reduced activity on unwanted side effects. The mechanisms responsible for the tissue-selective activity of SARMs are not fully understood, and the pharmacokinetic (PK)/pharmacodynamic (PD) relationships are poorly described. Tissue-specific compound distribution potentially could be a mechanism responsible for apparent tissue selectivity. We examined the PK/PD relationship of a novel SARM, LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin-7(6H)-one], in a castrated rat model of androgen deficiency. LGD-3303 has potent activity on levator ani muscle but is a partial agonist on the preputial gland and ventral prostate. LGD-3303 never stimulated ventral prostate above intact levels despite increasing plasma concentrations of compound. Tissue-selective activity was maintained when LGD-3303 was dosed orally or by continuous infusion, two routes of administration with markedly different time versus exposure profiles. Despite the greater muscle activity relative to prostate activity, local tissue concentrations of LGD-3303 were higher in the prostate than in the levator ani muscle. LGD-3303 has SARM properties that are independent of its pharmacokinetic profile, suggesting that the principle mechanism for tissue-selective activity is the result of altered molecular interactions at the level of the androgen receptor.
Combination treatment with a selective androgen receptor modulator q(SARM) and a bisphosphonate has additive effects in osteopenic female rats
J Bone Miner Res 2009 Feb;24(2):231-40.PMID:18847323DOI:10.1359/jbmr.081007.
Recent clinical trials with bisphosphonates and PTH have not supported the hypothesis that combination treatments with antiresorptive and anabolic agents would lead to synergistic activity. We hypothesized that combination treatment with a selective androgen receptor modulator (SARM), LGD-3303, and a bisphosphonate would be beneficial. In vitro competitive binding and transcriptional activity assays were used to characterize LGD-3303. LGD-3303 is a potent nonsteroidal androgen that shows little or no cross-reactivity with related nuclear receptors. Tissue selective activity of LGD-3303 was assessed in orchidectomized male rats orally administered LGD-3303 for 14 days. LGD-3303 increased the levator ani muscle weight above eugonadal levels but had greatly reduced activity on the prostate, never increasing the ventral prostate weight to >50% of eugonadal levels even at high doses. Ovariectomized female rats were treated with LGD-3303, alendronate, or combination treatment to study the effects on bone. DXA scans, histomorphometry, and biomechanics were performed. LGD-3303 increased muscle weight in females rats. In addition, LGD-3303 increased BMD and BMC at both cortical and cancellous bone sites. At cortical sites, the effects were caused in part by anabolic activity on the periosteal surface. At every measured site, combination treatment was as effective as either single agent and in some cases showed significant added benefit. LGD-3303 is a novel SARM with anabolic effects on muscle and cortical bone not observed with bisphosphonates. Combination therapy with LGD-3303 and alendronate had additive effects and may potentially be a useful therapy for osteoporosis and frailty.
A selective androgen receptor modulator enhances male-directed sexual preference, proceptive behavior, and lordosis behavior in sexually experienced, but not sexually naive, female rats
Endocrinology 2010 Jun;151(6):2659-68.PMID:20392832DOI:10.1210/en.2009-1289.
Androgens influence many aspects of reproductive behavior, including sexual preference of females for males. In oophorectomized women with sexual desire disorder, testosterone patches improve libido, but their use is limited because of adverse side effects. Selective androgen receptor modulators offer an improved safety profile for both sexes: enhancing libido and muscle and bone growth in a manner similar to steroidal androgens but with fewer adverse effects, such as hirsutism, acne, and prostate growth. The current study investigated the action of a novel selective androgen receptor modulator (LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one]) on male-directed sexual preference, proceptivity, and lordosis behavior of female rats. LGD-3303 is a nonsteroidal, nonaromatizable, highly selective ligand for the androgen receptor and effectively crosses the blood-brain barrier. Gonadectomized female rats were treated with LGD-3303 (3-30 mg/kg) or vehicle by daily oral gavage. Results showed that LGD-3303 treatment enhanced sexual preference of females for males but only if females had previous sexual experience. This occurred after 1 or 7 d of treatment. In contrast, preference for males was inhibited by LGD-3303 treatments of sexually naive females. The LGD-3303 increase in male preference was blocked by pretreatment with the androgen receptor antagonist flutamide. LGD-3303 treatment increased lordosis and proceptivity behaviors in ovariectomized females primed with suboptimal doses of estradiol benzoate plus progesterone. These data support the concept that LGD-3303 can stimulate aspects of female sexual behavior and may serve as a potential therapeutic for women with sexual desire disorders.
Identification of equine in vitro metabolites of seven non-steroidal selective androgen receptor modulators for doping control purposes
Drug Test Anal 2022 Feb;14(2):349-370.PMID:34714606DOI:10.1002/dta.3189.
Selective androgen receptor modulators, SARMs, are a large class of compounds developed to provide therapeutic anabolic effects with minimal androgenic side effects. A wide range of these compounds are available to purchase online and thus provide the potential for abuse in sports. Knowledge of the metabolism of these compounds is essential to aid their detection in doping control samples. In vitro models allow a quick, cost-effective response where administration studies are yet to be carried out. In this study, the equine phase I metabolism of the non-steroidal SARMs GSK2881078, LGD-2226, LGD-3303, PF-06260414, ACP-105, RAD-140 and S-23 was investigated using equine liver microsomes. Liquid chromatography coupled to a QExactive Orbitrap mass spectrometer allowed identification of metabolites with high resolution and mass accuracy. Three metabolites were identified for both GSK2881078 and LGD-2226, four for LGD-3303 and RAD-140, five for PF-06260414, twelve for ACP-105 and ten for S-23. The equine metabolism of GSK-2881078, LGD-2226, LGD-3303 and PF-06260414 is reported for the first time. Although the equine metabolism of ACP-105, RAD-140 and S-23 has previously been reported, the results obtained in this study have been compared with published data.