Novel nonsteroidal androgen receptor antagonist

[bornthisway]

Rational design and synthesis of 4-((1R,2R)-2-hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a novel, nonsteroidal androgen receptor antagonist devoid of phototoxicity for dermatological indications.

J Med Chem. 2008 Nov 13;51(21):7010-4. Epub 2008 Oct 16.

Li JJ, Iula DM, Nguyen MN, Hu LY, Dettling D, Johnson TR, Du DY, Shanmugasundaram V, Van Camp JA, Wang Z, Harter WG, Yue WS, Boys ML, Wade KJ, Drummond EM, Samas BM, Lefker BA, Hoge GS, Lovdahl MJ, Asbill J, Carroll M, Meade MA, Ciotti SM, Krieger-Burke T.

Department of Chemistry, Michigan Laboratories, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.

4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.

PMID: 18921992

 

[michael barry]

Department of Chemistry, Michigan Laboratories, Pfizer Global Research & Development,

... is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology.

a domestic RU58841, which would be very welcomed by yours truly...............there will have to be trials though, so we are talking 3-5 years for certain if they will get right on it like now

 

[Prevent99]

Michael, Is RU rapidly metabolized systemically?

 

[michael barry]

systemic effects were not evident with RU in macaques..........................I suppose Pfizer doesnt want to pay for the rights to RU and just came up with an androgen receptor antagonist on their own.



RU is supposedly very sensitive to water also. Someone that sweat a great deal who got caught in the rain might get less benefit that day. I wonder if humiditiy in the air might be problematic for RU negating the ability of someone to use it as a spray or whatever...................who knows. It would seem easier to just buy the rights to RU instead of coming up with an androgen receptor blocker or antagonist on your own, but then again.........ecgc and flutamide and spironolactone and lavender and tea tree and cyterperone acetate can all block androgen receptors and have done so in experiments so this company (Pfizer) probably wanted to make one themselves and get the moolah for it.


If the drug is approved for both acne and baldness........................it would be a double whammy. It could also be used to retard hairgrowth (on the back) and all that jazz too for someone who didn't want to laser out the hair on the back or shoulders, etc*****************

I hope they are going to trials and are gonna push it. I think MANY MANY more men would be willing to use a topical spray that "stopped baldness" in its tracks and had no "side effects" of the sexual nature. If minoxidil really "kept" your hair and it was acknoledged to do so , many more men would use it, but the perception is that it only works in the back, and only works for several years and then gets less effective----so it was a dud. Something that helps you keep your hair IN THE FRONT, that would have FDA APPROVAL would be much more "acceptable" for a man to use that didn't make him feel too metrosexualgirly in the process.



**************************I openly wonder if some of the people who do laser hair removal will have skin that ages badly. We have all of those vellus hairs on our skin for a reason. They are the signalling centers for skin renewal. Putting anti-androgens on the hairs that enlarge to terminal status might make them small over time, but wont "kill" them, so they can still give off skin-regenerating signals----but killing them with electricity or lasers just leaves skin. Your palms and feet dont have hairs, and they age pretty badly.
I oft think of some older white women that Ive seen in the past who plucked their moustaches over and over until the hair didn't grow there.......................but the tops of their mouths aged horribly with lines and wrinkles and were constantly dry to the point the ladies obviously put moisturizer up there. It looks like they have an extra a**h** on their face instead of a mouth becuase the lines are vertical. Ever notice that? I think we need those vellus hairs for skin regeneration, and I'd rather keep them small with a topical spray myself.

 

[goata007]

michael, does topically applied lavendar oil get into the blood stream or stays in the scalp?

 

[michael barry]

Ive not experienced any sides personally, but the possibility would exist if one used enough. It caused gyno in young boys who used it in body washes.


The NEJM researchers found that optimum concentrations were relatively low with the stuff. I think less than one percent........Im trying it on the right half of my chin now...............this should be the last thing I try. Its either this, green tea, or perhaps red clover tea. Thats about it thats "workable" in my opinion. A cotton seed oil might have some potential, etc. or some exotic substance with no anti-androgenic testing as of yet.

 

[Bryan]

RU is supposedly very sensitive to water also.

Where did you hear that, Michael? I've read almost all the available studies on RU58841, and I've never seen even a hint or suggestion of that.

 

[michael barry]

Bryan,

I looked around, because I remember reading that "somewhere", but found nothing on it. Perhaps I was thinking of fluridil.



Something that might interest you......................Ive only been putting lavender on the left side of my chin for about 3 weeks, but that side of my chin is very very dry, and the whiskers "feel" weaker than the other side. Its the same kind of feeling I had when using peppermint. I think lavender is going to be effective. Im running some green tea on one half of the moustache area. I want to get these little tests over with.

 

[el_duterino]

RU is supposedly very sensitive to water also.

Where did you hear that, Michael? I've read almost all the available studies on RU58841, and I've never seen even a hint or suggestion of that.

RU works fine in water, the lotion I use have distilled water in it.
I think one reason why RU was not considered is that it has some androgenic side effects due to one the plasma breakdown component.
It is a weaker but clearly anti-androgenic molecule with a longer half-life.

Granted, the side effects are nothing like flutamide, but since every other post on these forums seems to be from people complaining about sides, the manufactureres are taking note.

Side effects in my case are shrinkage of the prostate and a lower libido

The break-down component is produced at a very small amount but since it has a long-half life, it will build up in the blood and over time eventually some sides will appear.

 

[Bryan]

Bryan,

I looked around, because I remember reading that "somewhere", but found nothing on it. Perhaps I was thinking of fluridil.

I think that's probably it: you were confusing fluridil with RU.

Something that might interest you..........Ive only been putting lavender on the left side of my chin for about 3 weeks, but that side of my chin is very very dry, and the whiskers "feel" weaker than the other side. Its the same kind of feeling I had when using peppermint. I think lavender is going to be effective.

Somebody should do a Sebutape test on these substances.

 

[Bryan]

I think one reason why RU was not considered is that it has some androgenic side effects due to one the plasma breakdown component.

There's no indication in the literature of any significant side effects from RU.

Side effects in my case are shrinkage of the prostate and a lower libido

You can tell that you've had prostate shrinkage??

The break-down component is produced at a very small amount but since it has a long-half life, it will build up in the blood and over time eventually some sides will appear.

Again, there's no indication of that in the literature. It was used with stumptailed macaques for a long period of time (over a year) with no problem.

 

[cricketB]

In "androgen and androgens receptors" pdf by chang posted by Micheal time ago

( here is link but there is no more preview :
http://www.hairsite.com/hair-loss/forum ... nswer.html
)

we can read about some reduction of seminal vescicle.
I dont' remember exactly but i'm sure there is a little sentences about it .

Now i have no time to find the pdf.

For sure is not important but i 'm curious for any thoughts...

sorry for my poor english.

 

[goata007]

Something that might interest you......................Ive only been putting lavender on the left side of my chin for about 3 weeks, but that side of my chin is very very dry, and the whiskers "feel" weaker than the other side. Its the same kind of feeling I had when using peppermint.

I mix lavendar oil in olive oil and massage my scalp (leaving it overnight). After few weeks, my facial skin is definitely more drier now. E.g. After I wash my face with a cleanser skin has that dried look to it and it Never had that dried look with the same cleanser before.

I also want to thin my beard somewhat, how do you use it on your chin? do you mix it in water?

 

[el_duterino]

I think one reason why RU was not considered is that it has some androgenic side effects due to one the plasma breakdown component.

There's no indication in the literature of any significant side effects from RU.

[quote="el_duterino":2s8ndj6u]Side effects in my case are shrinkage of the prostate and a lower libido

You can tell that you've had prostate shrinkage??

The break-down component is produced at a very small amount but since it has a long-half life, it will build up in the blood and over time eventually some sides will appear.

Again, there's no indication of that in the literature. It was used with stumptailed macaques for a long period of time (over a year) with no problem.[/quote:2s8ndj6u]
Bryan, show us a study in HUMANS that prove that RU58841 has absolutley no sexual side effects..or did they test the libido in your monkeys !
We know about the anti-adrogenic break-down component of RU58841, in scientific litterature, not sure why you would question that.

The symptoms of Prostate shrinkage are: diffculty in stopping the flow of urine after urination..in other words pissing in your pants a bit.
The prostate size is the most sensitive factor to anti-androgens, a good measure for systemic absorbtion.
Again, did they test for prosate size of those macauques ?

 

[michael barry]

Goata,


yes...................I used about 1.5 milliliter of lavender oil with perhaps 30 milliliters of purified water and about 15 or so milliliters of everclear alchohol. Im probably using about a 4% concentration or thereabouts just guessing. I dont think you need much of the stuff. My chin is not only dry but the whiskers are losing circumference as compared to the other side. Im practically certain this is working, and it hasn't even been that long...


Back when I did the peppermint oil and water combo, I just used purified water






Bryan,

You are right about the sebutape. In fact, if I wasn't so confident about this substance, I'd have probably ordered some. But since it caused gyno in young boys who used body washes with it, and the New England Journal of Medicine tested it with androgen-sensitive cells and found it could block receptors as well as flutamide (even better actually)........................I was pretty confident that it would work. I'll probably be taking some pics of this in the coming months (let my beard grow out for a few days for a "difference shot" with both substances. I might even get some sebutape in a few weeks..............I'd like to nail this down and be done with it. I wanna "find" something of use for the guys and feel like I contributed "something" worthwhile for all the googling Ive down online about hair.

 

[jh]

michael barry,

Could you give a quick overview of what you have tried applying topically and your results? If I remember correctly, you've been testing topicals for a while.

Would testing sides of your face with sebutape strips give definitive proof something is an antiandrogen?

By the way, I think lavender is in the new folligen.

 

[SoThatsLife]

What would be the actual differences between this anti-androgen topical and the anti-androgen topicals we have today like spironolactone and RU? spironolactone is supposedly blocking androgen signals really effective and decrease DHT(can't remember if it was serum or scalp DHT) levels more than Propecia, but I have read that Dr. P says it still isn't as powerful as Propecia, at least not in the regrowth aspect which I guess is the only thing that would really make a product a success.

Many people, like Dr. Lee for one, have high hopes for ASCJ-9 that supposedly is going to destroy the androgen receptor in the skin, and then the androgen receptor rapidly reproduce itself, but it could be a "not every day" application of a topical drug that would be more easy to use than the available topicals. This would probably give a real good anti-androgen effect, but drugs like RU that have the almost "castrated" effect have some reported cases of people that have had a great experience the first 1-2 years and after 2 years it was a rapid decline in the hair density. Off course this could a coincident, and it only happed to a few unlucky. But it makes me think that a topical anti-androgen "attack" maybe triggers something over time. Are there any long time spironolactone-Only or RU-Only users?

(One could drag in Proxiphen as a spironolactone-related drug, but to my understanding, spironolactone is just a small "helper" in the mix of ingredients in Proxiphen. )

 

[michael barry]

michael barry,

Could you give a quick overview of what you have tried applying topically and your results? If I remember correctly, you've been testing topicals for a while.

Would testing sides of your face with sebutape strips give definitive proof something is an antiandrogen?

By the way, I think lavender is in the new folligen.

Ive tried peppermint oil/water topically and it had an extremely impressive reduction in my beard hair on the right side of my chin. However, Im afraid there might be something about peppermint that is bad for hair. Licorice for instance, has been tested and shown to be a strong androgen receptor antagonist and alpha five reductase antagonist by Japanese researchers, but some tests on rat's necks show licorice is just bad for hair period----as it severely reduced hair growth of hair that it apparently should have helped. There have been peppermint shampoos around for a while, and it peppermint was as good for hair as my little test seemed to indicate, there should be hair growth in evidence by now. When Ive used menthol shampoos in the past, I always thought my hair growth looked worse to be honest.


Ive tried Revivogen on one wrist before for three months (right wrist). It reduced the hair growth on that wrist, but it inflamed the area also. I have a feeling that something in Revivogen (maybe the alpha linolenci acid) is inflammatory and does as much harm as good. It certainly did reduce the arm hair though. I'll give it that.

I used Crinagen on the other wrist. It inflammed the wrist also......................and if there was any reduction in growth it was extremely slight.


I used pine oil (a lot of beta sitosterol in pine oil) on the back of one hand......................and it reduced the hair growth on that right hand some, but not as impressively as the revivogen.


I tried nizoral on my left wrist (wash and leave in for two minutes three times a week) for three months once. It made the wrist HAIRIER with longer darker hairs. This was a suprise.


I tried green tea right below the jawline for a couple of months a while back and the hair seemed weaker and lighter in color. It dried the skin out in that area also. Ive found the hair on the face proper is supposed to be more androgen sensitive.....................and think topicals are best tested there.



A long while back I tried lavender on toe hair for a few months. It was my right big toe. It actually made the hair longer and darker. This was a suprise. Lavender stimulates the estrogen receptor, so perhaps that hair is a bit estrogen sensitve. There is some perilla alchohol in lavender or some such substance that supposedly is "stimulative"..................so who knows. It certainly seems anti-androgenic on my chin thusfar (its quite dry), but its early. Id like to give it about three months. Growth phases are long in beard hair.



An anti-androgen should lessen beard hair because that hair is androgen sensitive........

 

[riptiduh]

Thanks again Michael.

I have been following these methods closely and do my own little concoctions at home. About a month ago I bought some Emu oil as I am desperately trying to regrow my hairline. I mixed it with a pinch of orange curcumin and 3 tablets of Jarrow Formulas Saw Palmetto. Slight changes, more peach fuzz and a few random hairs I didn't have before that are right in the middle of the bald spot...funny.

Recently, I bought 2 small bottles of the Emu Oil from Skinbiology.com along with some rosemary and lavender oil.
I poored a small amount of both oils in along with a pinch of curcumin and a smaller pinch of saw palmetto.

Honestly, from a month of the other emu oil not much has happened. I shaved my head when I did this so I didn't have to apply through long hair. Directly on the small bald spots in the front, there have been a couple new, random hairs that are growing back which I didn't have before. Besides that, a little more peach fuzz than previous. I know this won't be a cure all, hopefully the lavender and rosemary will add to whatever is going on.

I will be posting pictures soon of what it is right now and hopefully what it will turn into down the road. Truthfully, I do feel Emu with a pinch of curcumin and saw palmetto has done more good than harm. Exactly how much is in the eye of the beholder.

I forgot to mention I had 2 days with lavender in the Emu before I added rosemary. The rosemary oil definitely dried my hair out no question about it.

Wish I had more useful info...someone is bound to call out for pics, they will come soon enough.

 

[michael barry]

Would testing sides of your face with sebutape strips give definitive proof something is an antiandrogen

forgotten about that.....yes, if you found that less sebum (what sebutape strips measure) is being created after a few weeks of using a topical on your forehead, etc. , then that substance is probaby anti-androgenic unless its working to reduce sebum by some other mechanism (cell death or something way out there).