Selective androgen receptor modulators and methods of use thereof
An androgen receptor, selective technology, applied in the direction of diseases, pharmaceutical formulations, organic active ingredients, etc., can solve the problem of non-steroidal androgen reports and other issues
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Embodiment 1
[0187] Non-steroidal ligands with androgenic and anabolic activity
[0188] The SARM compounds provided herein were designed, synthesized, and evaluated for their in vitro and in vivo pharmacological activities. In vitro androgen receptor binding affinity and ability to maintain androgen-dependent tissue growth in castrated animals were studied. Androgenic activity is monitored by the ability of the SARM compounds to maintain and / or stimulate prostate and seminal vesicle growth, which is measured gravimetrically. Anabolic activity is monitored by the ability of the SARM compounds to maintain and / or stimulate the growth of the levator ani muscle measured gravimetrically.
[0189] The synthetic process of compound I-VIII:
[0190] (2R)-1-methacryloylpyrrolidine-2-carboxylic acid (R-129). Dissolve D-proline (R-128, 14.93 g, 0.13 mol) in 71 mL of 2N NaOH and store on ice Cool in a bath; dilute the resulting basic solution with acetone (71 mL). A solution of methacr...
Embodiment 2
[0199] Non-steroidal ligands with androgenic and anabolic activity
[0200] The in vivo efficacy and acute toxicity of four new non-steroidal androgens (compounds IV, V, VI and VII) were examined in rats. In vitro experiments confirmed that these compounds bind the androgen receptor with high affinity. The structures and names of the four compounds are as follows:
[0201]
[0202] GTx-014 R=F
[0203] GTx-015 R=COCH 3
[0204] GTx-016 R=COC 2 h 5
[0205] GTx-007 R=NHCOCH 3
[0206] experiment method
[0207] material.according to Figure 9 The shown route synthesizes compound GTx-014 (compound IV), GTx-015 (compound V), GTx-016 (compound VI) and GTx-007 (compound VII, wherein R is NHCOCH 3 ) and the R-isomer of GTx-014. Testosterone propionate (TP), polyethylene glycol 300 (PEG300, reagent grade) and neutral buffered formalin (10% w / v) were purchased from Sigma Chemical Company (St Louis, MO). Alzet os...
Embodiment 3
[0224] Pharmacokinetics of GTx-007 in dogs
[0225] The pharmacokinetics of S-GTx-007, a novel selective androgen receptor modulator (SARM), were characterized in beagle dogs. A four-treatment, four-period crossover design was used in the study involving a total of six beagles, three of each sex. Each animal received a 3 mg / kg IV dose, a 10 mg / kg IV dose, a 10 mg / kg PO dose in solution and a 10 mg / kg PO dose in capsules in the order of random allocation. There is a one-week washout period between treatments. Plasma samples were collected up to 72 hours after drug administration. Plasma S-GTx-007 concentrations were analyzed by a certified HPLC method. Determination of clearance (CL), volume of distribution (Vss), half-life (T 1 / 2 ) and other pharmacokinetic parameters. The results showed that after IV administration, S-GTx-007 cleared terminal T from canine plasma. 1 / 2 About 4 hours, CL is 4.4mL / min / kg. Figure 4 , 5 and 6 show the plasma concentration-ti...
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