FIRST-TIME DISCLOSURES OF CLINICAL CANDIDATES
Frailty, erectile dysfunction, scarring, and thrombosis/atherosclerosis drugs introduced
...In frail patients, low muscle strength is often associated with low blood levels of the male hormone testosterone. Testosterone is sometimes administered to men with symptoms of muscle wasting and age-related functional decline. However, the hormone can also have "hyperstimulatory" effects on the prostate, which can exacerbate preexisting prostate cancer and benign prostatic hyperplasia (noncancerous enlargement of the prostate).
IN ADDITION, Hamaan noted that testosterone cannot be given orally because it's rapidly metabolized. It therefore has to be administered as a patch or gel. Patches are optimally applied genitally, a form of administration that patients often dislike. And testosterone in gels can be transferred inadvertently to people who come in contact with the patient's skin.
A potential alternative to testosterone is the use of SARMs (selective androgen receptor modulators), compounds with activity similar to that of testosterone and other male hormones. SARMs are being investigated for treatment of hormone-related conditions in men--such as age-related functional decline, hypogonadism (hormone deficiency), benign prostatic hyperplasia, and andropause (ADAM, for "androgen decline in the aging male")--as well as conditions in both men and women, such as osteoporosis and sexual dysfunction. The corresponding treatments aimed at hormone-related conditions in women are SERMs (selective estrogen receptor modulators).
Hamann and coworkers at BMS have discovered a series of SARMs that are orally active and can potentially improve muscle strength and function with reduced risk of prostate hyperstimulatory effects. Studies in rodents of one of these agents, BMS-564929, showed that it is 230 times more potent than testosterone. In addition, it is 160-fold more selective for muscle-strengthening effects over prostate-stimulatory effects, compared with the twofold selectivity of testosterone. "So theoretically you can push the dose higher to see beneficial effects before you would begin to see any deleterious effects" such as prostate hyperstimulation, Hamann said. "This has the potential to really be a useful approach in an area of unmet need."
To find BMS-564929, BMS scientists did a computer analysis of known steroids and other small molecules that exhibit activity at androgen receptors and developed a four-point pharmacophore--a model of four structural and energetic drug features associated with the receptor interactions. They selected a library of 1,400 compounds from the BMS compound library that fit the model and screened them for activity.
"Out of that came some novel scaffolds, which we then elaborated with classical medicinal chemistry to arrive at the molecules we currently have," Hamann said. The best among these was BMS-564929, which is "currently in human clinical trials for indications of age-related functional decline in men," he said....
230x more potent and 160x more selective than test... this is the fashizzle!
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Originally Posted by Flack
