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

Inactive Publication Date: 2005-12-07
UNIV OF TENNESSEE RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although non-steroidal antiandrogens are clinically used in hormone-dependent prostate cancer, no non-steroidal androgens have been reported

Method used

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  • Selective androgen receptor modulators and methods of use thereof
  • Selective androgen receptor modulators and methods of use thereof
  • Selective androgen receptor modulators and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

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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Abstract

This invention provides a novel class of androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds which are tissue-selective androgen receptor modulators (SARM), which are useful for oral testosterone replacement therapy, male contraception, maintaining sexual desire in women, treating prostate cancer and imaging prostate cancer. These agents have an unexpected in-vivo activity for an androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. These agents may be active alone or in combination with progestins or estrogens. The invention further provides a novel class of nonsteroidal agonist compounds and methods of binding an androgen receptor, modulating spermatogenesis, treating and imaging prostate cancer, and providing hormonal therapy for androgen-dependent conditions.

Description

technical field [0001] The present invention relates to a new class of tissue selective androgen receptor targeting agents (ARTAs) which exhibit androgenic and anabolic activity of non-steroidal ligands of the androgen receptor. Targeted Agents Definition Those are a new subclass of compounds that are Tissue Selective Androgen Receptor Modulators (SARMs) that are useful in androgen therapies such as oral testosterone replacement therapy, male contraception, maintenance of libido in women, treatment of prostate cancer and imaging of prostate cancer it works. These agents are also administered to subjects for the treatment of sarcopenia, loss of libido, osteoporosis, erythropoiesis, and fertility. Targeting agents can be used alone or in combination with progesterone or estrogen. Background technique [0002] The androgen receptor ("AR") is a ligand-activated transcriptional regulatory protein that mediates male sexual development and function through its endogenous androgen...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61P5/28A61K31/167A61K31/404A61K31/4706A61K31/661A61P7/06A61P13/08A61P15/00A61P15/08A61P15/16A61P19/10A61P35/00C07C235/24C07D209/08C07D215/22C07D215/227C07D271/12G01N33/543G01N33/74
CPCG01N33/5438G01N33/74C07D271/12C07C235/24A61K31/661A61K31/167C07D209/08C07D215/227A61K31/404A61K31/4706A61P13/08A61P15/00A61P15/08A61P15/16A61P17/14A61P19/10A61P35/00A61P43/00A61P5/26A61P5/28A61P7/06
Inventor 詹姆斯·多尔顿杜安·D·米勒尹东华何雅丽
Owner UNIV OF TENNESSEE RES FOUND
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