AR (IC50 = 6.6 nM)
MK-0773 targets the androgen receptor (AR), a nuclear receptor that mediates the effects of androgens such as testosterone and dihydrotestosterone. As a selective androgen receptor modulator (SARM), MK-0773 binds to the AR and modulates its activity. Unlike traditional androgens, SARMs are designed to provide tissue-selective effects, promoting anabolic effects in muscle and bone while minimizing androgenic effects in other tissues such as the prostate and skin. MK-0773 binds to AR with an IC50 of 6.6 nM.

MK-0773 binds to serum proteins as evidenced by its increased IC50 of 3.5 times when 3.5 percent rat serum and 13 times when 25% human serum are present. Using COS cells transfected with AR, the affinity of MK-0773 for AR is assessed across species. The IC50 values(0.50 nM for rats, 0.55 nM for dogs, 0.45 nM for rhesus, and 0.65 nM for humans) in all four species are remarkably similar[1].

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In vitro, MK-0773 demonstrates potent binding affinity for the androgen receptor with an IC50 of 6.6 nM. As a SARM, the compound is expected to activate AR-mediated transcriptional activity in a tissue-selective manner. Specific cellular assay data, such as EC50 values for transcriptional activation in different cell types, are not detailed in the available sources. The compound's selectivity for AR over other steroid hormone receptors is a key characteristic of its SARM profile.

In the OVX rat model, MK-0773 (6 and 80 mg/kg, s.c.) causes exposure-related stimulatory effects on cortical BFR and LBM. MK-0773 has less of an impact on the prostate and raises the weight of seminal vesicles at doses of 5, 15, and 80 mg/kg, s.c. In OVX rats, MK-0773's partial agonism and tissue selectivity do not result in different effects on lipid metabolism[1].

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MK-0773 was dosed subcutaneously for 24 days in the OVX rat model (6 and 80 mg/kg) and produced plasma exposures over 24 h of 6.6 and 62 μm·h (Fig. 5b). This treatment produced exposure-related stimulatory effects on cortical BFR and LBM. The maximal anabolic effects of MK-0773 were equivalent to the SARM TFM-4AS-1 and ∼80% of 3 mg/kg DHT. Both MK-0773 and TFM-4AS-1 had <5% of the effect on uterus weight, and about 30–50% of the increase of sebaceous gland area produced by 3 mg/kg DHT. Next, ORX male rats were treated with daily subcutaneous dosing with MK-0773 (5, 15, and 80 mg/kg) for 17 days. The treatments produced plasma exposures over 24 h of 3, 10, and 56 μm·h. At the highest exposure tested, MK-0773 increased seminal vesicle weights by 12% that achieved by 3 mg/kg DHT (Fig. 5c and Table 2) and had similarly reduced effects on the prostate (data not shown). Taken together, MK-0773 exhibits the profile of an anabolic SARM with limited effects on the sebaceous glands and reproductive tracts of OVX and ORX rats[1].

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Effect of MK-0773 and 2-FPA on Cholesterol In humans anabolic androgens reduce high density lipoprotein cholesterol by mechanisms that are not understood but have been proposed to reflect changes in lipid metabolism in adipose tissue. We, thus, asked if SARMs developed by our method would also reduce cholesterol levels in preclinical models. Treatments of OVX rats with MK-0773, 2-FPA, TFM-4AS-1, and DHT at anabolic doses for 24 days resulted in a similar decline in both total cholesterol and high density lipoprotein by 25–37% (Table 3). Thus, the partial agonism and tissue selectivity of MK-0773 does not translate into differential effects on lipid metabolism in OVX rats[1].

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MK-0773 was evaluated in a clinical study for the treatment of sarcopenia (loss of muscle mass) in women. A study titled "A Study of the Safety and Efficacy of MK-0773 in Women With Sarcopenia (Loss of Muscle Mass) (MK-0773-005)" was conducted. Specific in vivo efficacy data from animal models are not detailed in the available sources. The compound's progression to clinical studies indicates promising preclinical activity for muscle wasting conditions.

Binding and Transcription Assays[1]
Binding and transactivation assays used the human breast carcinoma cell line MDA-MB-453, which expresses endogenous AR. ARBIND assays with 0.5 nm [3H]methyltrienolone (R1881, a potent AR agonist) were as previously described. TAMAR assays (transactivation modulation of AR) in 96-well plates used transient transfection of a modified mouse mammary tumor virus (MMTV) long terminal repeat promoter upstream of luciferase (MMTV-LUC). This MMTV has two direct repeat copies of a consensus glucocorticoid receptor response element between positions −88 and −190; these sequences are also recognized by AR. The VIRCON (virilization counterscreen) assay, which measures the AR N-terminal domain/ligand binding domain (LBD) interaction (N/C) of rhesus AR (rhAR), was evaluated by a mammalian two-hybrid assay in CV1 cells as detailed in Schmidt et al. The N/C interaction was evaluated as a ligand-mediated increase of luciferase reporter activity.
The TRAF2 (transcriptional recruitment to AF2) assay, which measures the activation mediated by the AF-2 domain and potentiated by the full-length rat GRIP-1 coactivator, was measured by a mammalian two-hybrid assay in similar manner to the VIRCON assay. The Gal4-DNA binding domain was fused with the LBD of rhAR (pm-rhAR-LBD, amino acids 637–895), and the VP16AD was fused to the rat GRIP-1 (pcDNA3-GRIP-1 plasmid). The luciferase reporter plasmid with 5 copies of GAL-4 DBD binding sites (Gal4 × 5X90-luciferase) was transfected into COS-1 cells with the pm-rhAR-LBD and pcDNA3-GRIP-1 plasmids, and the AF-2 function was evaluated as a ligand-dependent dose response.

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The androgen receptor binding assay for MK-0773 involves incubating the compound with a source of androgen receptor (such as cytosol from prostate tissue or recombinant AR) and a radiolabeled androgen ligand (such as [³H]-R1881 or [³H]-DHT). After incubation at 4°C for an appropriate period, bound and free ligands are separated using a charcoal-dextran method or filtration. The radioactivity is counted, and the IC50 for displacement of the radioligand is calculated from the competition curve.

To evaluate the cellular activity of MK-0773, cells expressing the androgen receptor (such as prostate cancer cell lines or cells transfected with AR) are seeded in 96-well plates. Cells are treated with varying concentrations of MK-0773, and AR-mediated transcriptional activity is measured using a reporter gene assay (such as an androgen-responsive element (ARE)-luciferase reporter). The EC50 for transcriptional activation is calculated. The compound's tissue selectivity can be assessed by comparing its activity in different cell types or by using different promoter contexts.

Rats: After an orchidectomy (ORX), 3–4-month-old, 250–300-g rats' prostate and seminal vesicles are examined. Following surgery, the animals receive daily subcutaneous injections of test compounds for a period of 17 days. The weight of the seminal vesicles (SVs) is compared to that of ORX rats that were treated with either vehicle or DHT as a positive control.

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Specific in vivo animal experiment protocols for MK-0773 are not detailed in the available sources. As a SARM, the compound would typically be evaluated in animal models of muscle wasting or osteoporosis. Orchidectomized (castrated) male rats or aged female rats would be treated with MK-0773 orally at various doses. Muscle mass (such as levator ani muscle weight) and bone mineral density would be measured as indicators of anabolic activity. Androgenic effects would be assessed by measuring prostate and seminal vesicle weights. However, specific protocols are not described in the available literature.

Specific pharmacokinetic data for MK-0773 are not provided in the available sources. The compound is a small molecule with a molecular weight of approximately 479.6 and a molecular formula of C27H34FN5O2. It is soluble in DMSO at 33.33 mg/mL. As a powder, it is stable at -20°C for 3 years and at 4°C for 2 years. Standard pharmacokinetic studies would typically involve administering the compound to rodents and measuring plasma concentrations over time using LC-MS/MS.

Specific toxicity data for MK-0773 are not provided in the available sources. However, the compound was evaluated in a clinical study for the treatment of sarcopenia in women, indicating that its safety profile has been assessed in humans. As a research compound, it is intended for laboratory use only and is not approved for human therapeutic applications. Standard safety precautions should be followed when handling this compound.

[1]. Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology. J Biol Chem. 2010 May 28;285 .

MK-0773 is being investigated in the clinical trial NCT00529659 (a study on the safety and efficacy of MK-0773 in women with sarcopenia (low muscle mass)) (mk-0773-005).

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MK-0773 is a selective androgen receptor modulator (SARM) and 4-aza-steroid that exhibits potent tissue selectivity. It binds to the androgen receptor with an IC50 of 6.6 nM. It was studied for the treatment of sarcopenia (loss of muscle mass) in women in a clinical study (NCT00529659). The compound has a molecular formula of C27H34FN5O2 and a UNII of 5730VNW22X.

C27H34FN5O2

479.589569568634

479.269

C, 67.62; H, 7.15; F, 3.96; N, 14.60; O, 6.67

606101-58-0

606101-58-0

11950726

Light yellow to yellow solid powder

1.3±0.1 g/cm3

754.2±60.0 °C at 760 mmHg

409.9±32.9 °C

0.0±2.5 mmHg at 25°C

1.632

3.17

2

5

3

35

927

7

FC1C(N(C)[C@]2([H])CC[C@]3([H])[C@]([H])(CC[C@]4(C)[C@@H](C(N([H])CC5=NC6=C(C=CC=N6)N5[H])=O)CC[C@]43[H])[C@]2(C=1)C)=O

GBEUKTWTUSPHEE-JWJWXJQQSA-N

InChI=1S/C27H34FN5O2/c1-26-11-10-17-15(6-9-21-27(17,2)13-19(28)25(35)33(21)3)16(26)7-8-18(26)24(34)30-14-22-31-20-5-4-12-29-23(20)32-22/h4-5,12-13,15-18,21H,6-11,14H2,1-3H3,(H,30,34)(H,29,31,32)/t15-,16-,17-,18+,21+,26-,27+/m0/s1

(1S,3aS,3bS,5aR,9aS,9bS,11aS)-8-fluoro-N-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-6,9a,11a-trimethyl-7-oxo-2,3,3a,3b,4,5,5a,9b,10,11-decahydro-1H-indeno[5,4-f]quinoline-1-carboxamide

MK0773; MK-0773; MK 0773; PF 05314882; CHEMBL3221237; 5730VNW22X; PF05314882; PF-05314882

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~33.3 mg/mL (~69.5 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.21 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)