14 replies to this topic

[tom a]

Here's an article with some useful details about resveratrol research at Sitris.

http://money.cnn.com...sion=2007011912

[makoss]

"If I had $500 million today," says Westphal, "I'd be tempted to take our drugs into the clinic against two or three devastating neurological conditions and other metabolic diseases besides diabetes

The above quote was from the Fortune article. Wouldn't it be great if Bill Gates could redistribute some of the money he has donated to find a cure for AIDS and end famine, to the Sinclaire study. He could be a part of the greatest find in medical history, one that may even cure AIDS.

[curious_sle]

Uh, cure AIDS? Huh? Well, St. Johns Worth seems to be a herb that could be developed further into a AIDS drug perhaps but Resveratrol? How so?

[makoss]

A cure? Who really knows the soup to nuts potential of ResV. REsV might help relieve certain drug side effects, or other problems resulting from HIV disease, including lipid or other metabolic abnormalities, or neuropathy, or other symptoms suspected of being caused by mitochondrial damage.

Edited by makoss, 20 January 2007 - 09:36 PM.

[tom a]

From the article:

Meanwhile, hoping to get an early indication of efficacy against disease, the company formulated a resveratrol-based drug, dubbed 501, to begin the tests in diabetic patients. Westphal cautions that the drug is likely to be a product for only a few indications - Sirtris's more potent medicines will probably have much broader applications. Still, in animal tests, 501's proprietary formulation gets more than ten times as much resveratrol into the bloodstream as do dietary supplements containing equal amounts of it, says the company.

What I find interesting about this point is that it seems to indicate that Sitris and Sinclair seem to think that resveratrol's effect is much enhanced by adding additional molecules to get it into the bloodstream. This was I gather the motivation for adding quercetin into the Longevinex formula (in which Sinclair, I believe, was involved).

It seems that even at this stage of the game Sinclair and the other scientists involved appear to believe that that is the right thing to do, rather than stick with pure resveratrol -- even though the recently published mice studies were of course based on pure resveratrol.

[curious_sle]

Tom a, what Sinclair et all did is create variants of Resveratrol replacing the 4' position. Their work thus far looks good.

Try to get Doi: 10.1111/j.1474-9726.2006.00259.x "Design an Synthesis of compound that extend yeast replicative lifespan" Published in Aging Cell in 2006.

[tom a]

curious_sle,

How sure are you that the 501 compound is the one described in the article you referred to?

I guess I had naively assumed that "resveratrol-based" meant that resveratrol itself as a pure molecule was present in the drug, not that the resveratrol molecule itself had been altered.

[curious_sle]

Well, there is no mention of "501" in the mentioned article so i have no idea really. Why it is not straight Resveratrol? They shoot for higher potentcy and of course for patentability. If i read it right they achieved several times higher effect and a lot lower toxicity so essentially you could reach say ten times the effect of resveratrol with their compounds. Lifespan studies using the new analogues will take a long time before resulting in something publishable.

[maxwatt]

SRT-501 in cliinical trials. Phase 1-a was completed in October.

http://www.pipeliner.../view/7094/114/

[niner]

501's proprietary formulation gets more than ten times as much resveratrol into the bloodstream as do dietary supplements containing equal amounts of it, says the company.

This wording says to me that 501 is just resveratrol mixed with other things to improve its bioavailability. This is a common practice for compounds like resveratrol that have poor water solubility. In the pharmaceutical world, the word "formulation" has a very specific meaning: it means the stuff the compound is mixed with in order to alter its pharmacokinetics, like an "extended release formulation". The quote also talks about getting "resveratrol" into the bloodstream. On the other hand, what I can garner from quickly googling srt501, while vague, suggests that the structure has been modified. At this point, I really couldn't tell you what 501 is. If it's just a suspension of resveratrol in oil or some commonly available substance, that's something we could do ourselves. If it's a chemical modification of the molecule, then fuggedaboudit. I'm inclined to believe that the quote above is from a reporter who doesn't know the jargon and just got it wrong; that is to say that 501 is a different molecule than resveratrol. The fact that it has a Sirtris reference code in the 500's would normally mean that it was the 501st compound they have entered in their registration system, and I would expect resveratrol to be in the single digits. (Unless they started numering at 500..., or register formulations...)

[curious_sle]

From the aforementioned article. No reference to which is which Drug candidate however.

"In agreement with previous reports (Howitz et al ., 2003; de Boer et al ., 2006), resveratrol (50 μ M ) stimulated the activity of SIRT1 ∼ 12-fold (Fig. 3). Derivative 1 (3,5-dihydroxy-4’-thiomethyltrans-stilbene), in which the 4’-hydroxyl was replaced with a thiomethyl group, was the most effective, stimulating SIRT1 activity 18-fold, while Derivative 4 (3,5-dihydroxy-4 ′ -methoxytrans -stilbene), bearing a chemically similar methoxy group activated SIRT1 11-fold (Fig. 3). Derivative 2 (3,5-dihydroxy-4’-methyltrans-stilbene) and Derivative 3 (3,5-dihydroxy-4’-ethyltrans-stilbene), substituted with hydrophobic methyl and ethylgroups at the 4’ positions, activated SIRT1 16- and 14-fold, respectively. Derivative 5 (3,5-dihydroxy-4’-acetoxytrans-stilbene), bearing an ester group with a relatively large volume at the 4’position was the least potent, stimulating SIRT1 only threefold. Based on this structure–activity relationship, it appears that small, hydrophobic substituents at the 4’ position can enhance the potency of stilbenes."
"

but i can wager a guess based on

"
The activity of a STAC in vivo will depend on many factors such as its rate of uptake and metabolism. For this reason,
in vitro activity may not always correlate with the ability to activate sirtuins in cells. For example, in vivo esterases are known to readily cleave off acetyl groups from acetyl-containing molecules to release acetate (White & Hope, 1984). For this reason drugs are often acetylated in a prodrug form as a means of enhancing its properties, such as stability, without diminishing its biological activity (Takahashi et al., 1992). Derivative 5, which is acetylated at the 4’ position, was the least efficacious of the STACs in activating SIRT1 in vitro, although the lifespan extension it produced was the largest achieved by treatment with a STAC to date, possibly because it remains more stable in the yeast medium than other STACs and is cleaved by esterases once it enters the cell, releasing free resveratrol and acetate and providing a steady
stream of the active compound, but clearly more experiments will be required to confirm this.
"

edit: formating...

:-)

[maxwatt]

"
The activity of a STAC in vivo will depend on many factors such as its rate of uptake and metabolism. For this reason,
in vitro activity may not always correlate with the ability to activate sirtuins in cells. For example, in vivo esterases are known to readily cleave off acetyl groups from acetyl-containing molecules to release acetate (White & Hope, 1984). For this reason drugs are often acetylated in a prodrug form as a means of enhancing its properties, such as stability, without diminishing its biological activity (Takahashi et al., 1992). Derivative 5, which is acetylated at the 4’ position, was the least efficacious of the STACs in activating SIRT1 in vitro, although the lifespan extension it produced was the largest achieved by treatment with a STAC to date, possibly because it remains more stable in the yeast medium than other STACs and is cleaved by esterases once it enters the cell, releasing free resveratrol and acetate and providing a steady
stream of the active compound, but clearly more experiments will be required to confirm this.
"

edit: formating...

:-)

VERY nice catch.

[curious_sle]

my pleasure. read the whole article if you can get it.

[niner]

Thanks for the SAR, curious_sle! The prodrug approach would be consistent with the wording "ten times as much resveratrol into the bloodstream..." It's a good guess for the identity of 501. I'm beginning to wonder how tough it would be to synthesize these relatively simple stilbenes.

[malbecman]

From my reading of the lit., it sounds like absorption of ResV from the gut is not the problem, it is the rapid metabolism to the glucuronide and sulfate metabolites (so there is no free ResV circulating). This would occur in the intestinal epithelial cells as well as the liver which receives the blood from the GI.

Sulfate and glucuronide metabolism occurs (attach) at the hydroxy groups (OH) of resveratrol. It is quite common to make a drug more stable/longer lasting in the bloodstream by blocking the OH group to sulfate and glucuronode metabolism. This is usually achieved by adding a methyl or ethyl group or somesuch to the OH groups and making a methyl/ethyl ester which cannot be sulfated/glucuronidated. The net effect is to have more free ResV circulating in the bloodstream and doing all of its good stuff. This is what it sounds like was done with ResV by Sirtis, et al....

It also has the positive effect that is also makes the drug a little more nonpolar so it can pass across lipid bilayers of cells more easily.

Just my 2 cents from studying pharmacology and metabolism in grad school,

Cheers,

Malbec