| Pages:
1
2
3 |
syed
Harmless
Posts: 2
Registered: 11-1-2007
Member Is Offline
Mood: No Mood
|
|
SILDENAFIL CITRATE
hey guys i doing a project on Sildenafil Citrate and i finally found out all the functional groups but i have no clue what the functional groups do to
make viagra viagra. I know theres a ether group, amine, amide, sulfonyl group, sulfonamide, a benzene ring, and finally an alkene but i dont know what
these do.
[Edited on 12-1-2007 by syed]
|
|
|
bereal511
Hazard to Others
Posts: 162
Registered: 9-8-2005
Location: Madison, WI
Member Is Offline
Mood: No Mood
|
|
All parts of the sildenafil molecule takes on a shape designed to selectively bind to the enzyme cGMP specific phosphodiesterase, which catalyzes the
destruction of the guanosine monophosphate in the body. With cGMP specific phosphodiesterase disabled in the body, guanosine monophosphate is free to
act on the muscle cells in the penis, which causes muscle relaxation. This in turn allows blood to flow more freely, giving erections. Now, if you
wanted how each individual functional group attaches to the enzyme mentioned beforehand, you should probably research more in depth on the binding
mechanisms of sildenafil and the corresponding chemical structure of phosphodiesterase. There's not much that the functional groups do on their own
to lock onto the enzyme, its the structure of sildenafil as a whole, though the nitrogenous and oxygenated functional groups play the strongest role
in their Van der Waals attractions to the enzyme.
As an adolescent I aspired to lasting fame, I craved factual certainty, and I thirsted for a meaningful vision of human life -- so I became a
scientist. This is like becoming an archbishop so you can meet girls.
-- Matt Cartmill
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
Be aware that sildenafil only works (promoting vasodilation) on males who suffer from specific typed of erectile dysfunction. And then it only works
if the subjects have external erotic stimulation.
In short if you don't need it, it does nothing, and if you aren't being stimulated it still does nothing. It is not an aphrodisiac.
The synthesis of sildenafil is rather long and complex.
There is now a true human aphrodisiac, one that directly stimulates the libido and it is effective on both men and women, It is not a vasodilator. It
is a synthetic cyclo heptapeptide analog of alpha-melanocyte stimulating hormone. and it is called Bremelanotide or PT-141,
It has the structure:
Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-OH
All those seven amino acids are L-isomers except for the D-Phe.
This stuff is in FDA Phase III trials already as treatment for female sexual dysfunction. It belongs to Palatine Technologies of New Jersey.
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
And the three rings in sildenafil are a pyrazine, a substituted phenol and a piperazine.
One of my Irish friends is the process engineer at Pfizer in Dublin where they used to make the stuff. Now they have licensed it out and are busy
making Lipitor there.
The original, and the improved Pfizer processes for sildenafil were posted on Rhodium and are in the literature. There are no trade secrets involved.
It is widely knocked off in bulk in India, China and North Korea, also Cambodia. Bulk sildenafil citrate sells for about $2000 a Kg. Having studied
the prep in detail I would not make it for that price. Too damned much work.
[Edited on 12-1-2007 by Sauron]
|
|
|
Polverone
Now celebrating 21 years of madness
Posts: 3186
Registered: 19-5-2002
Location: The Sunny Pacific Northwest
Member Is Offline
Mood: Waiting for spring
|
|
| Quote: | Originally posted by Sauron
Be aware that sildenafil only works (promoting vasodilation) on males who suffer from specific typed of erectile dysfunction. And then it only works
if the subjects have external erotic stimulation.
In short if you don't need it, it does nothing, and if you aren't being stimulated it still does nothing. It is not an aphrodisiac.
The synthesis of sildenafil is rather long and complex.
There is now a true human aphrodisiac, one that directly stimulates the libido and it is effective on both men and women, It is not a vasodilator. It
is a synthetic cyclo heptapeptide analog of alpha-melanocyte stimulating hormone. and it is called Bremelanotide or PT-141,
It has the structure:
Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-OH
All those seven amino acids are L-isomers except for the D-Phe.
This stuff is in FDA Phase III trials already as treatment for female sexual dysfunction. It belongs to Palatine Technologies of New Jersey.
|
Now there's a license to print money. How is it synthesized? I know little about peptide chemsitry, but I do know what sort of spam will be clogging
my inbox in a few years.
PGP Key and corresponding e-mail address
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
You don't need a crystal ball to see that one coming, for sure. The Indians and the Chinese (The Usual Suspects in this racket) are already on it.
Peptide synthesis is not a cakewalk. At the minimum the stereochemical issues are daunting, HPLC requires a pretty serious investment on a preperative
scale, the protecting group selection and coupling strategy decisionmaking is tricky, and in the case of this relatively simple heptapeptide, the
cyclizing step is low yield.
Life's a bitch.
I am leaning toward Fmoc strategy rather than Boc.
I have about $40,000 invested in second hand Waters analytical and prep HPLC systems at this point. And that is on a scale to clean up grams per
injection.
This is my major project, it is quite challenging and I will be at it for years (already about 1.5 years). I have zero ambition to sell it, I just
want to see if I am good enough to make it and purify it. It does have the advantage over some other challenging molecules of not being illegal and of
not requiring any suspicious reagents (unless D-Phenylalanine is.)
One of the amino acids, Nle (L-Norleucine) is not very available commercially. It is easy to make in racemic form and the problem then is to resolve
it. Best done enzymatically with papain Nle is an unnatural amino acid used as an internal standard in instrumental analysis of amino acids, To build
it, you alpha-brominate caproic acid, treat that with conc ammonium hydroxide and you have DL-Nle. That much is dead simple. It's all in Org.Syn. The
enzymatic resolution is in J.Biol.Chem. and can be had for free online.
All the other amino acids are off the shelf.
I am digitizing two great books on peptide synthesis by M.Bodanszky, one is a text and the other a lab manual. Eventually I will upload these to
MadHatter.
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
The hormone a-MSH from which Bremalonotide is derived is produced in the human posterior pituitary and as the name "melanocyte stimulation hormone"
implies it regulates skin pigmentation (melanin). Most reptiles, amphibians, fish and all mammals have MSH, a 13-amino acid peptide. The first six
residues are species specific. The last seven are the business end and are always the same. Bremelanotide is a modification of that part of a-MSH. The
Univ. of Arizona was after an oral sunless tanning agent (take a pil, get a sun tan) so that people who wanted a tan would not have to sunbathe or sit
under UV lamps and be at risk of skin cancer. They came up with two products, Melanotan and Melanotan-II. The latter had an unexpected side effect. It
made test subjects horny. Further tsting demonstrated that it induced erections even in older males with erectile dysfunction (ED) and that it also
produced an erotic response in women. This effect occurs in complete absence of external stimulation unlike Viagra etc, and this substance, now given
the generic name Bremelanotide, is regarded as the first of an entirely new class of pharmaceutical agents and is on a fast track to FDA approval. The
development of the sunless tanning agent has been seperated from that of the aphrodisiac; Bermelanotide does not give you a tan and Melanotan-II no
longer makes you horny. The Bremelanotide side is licensed exclusively to Palatine Technologies who call it PT-141.
The ED is 20 mg. Higher doses induce nausea.
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
Although peptide chemistry is difficult there are many many commercialized pharmaceuticals that are peptides and the pharm industry mass produces
them, purifies them by HPLC, they know what they are doing. Many of these are substantially more complex than Bremelanotide. 10-20 amino acids
compared to only 7 in Bremelanotide. Human insulin is over 100 amino acids. It is now produced synthetically.
Reverse phase HPLC can seperate insulins that differ by a single methyl group. One -CH3 in a peptide of 100 amino acids. Incredible. In RP there is a
pH gradient and the individual peptides fall off the stationary phase one by one as the pH changes.
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
Here's food for thought.
Serendipitous discoveries like the unexpected side effect of Bremelanotide, rarely are fully optimized for the specific effect.
That means there is a lot of SAR yet to be done. (Structure-activity relationships). But what this discovery has done, is to open the door to direct
stimulation of primary human emotions.
If we can (accidentally at first) trigger the libido, perhaps we can manipulate gender identiry. Perhaps we can have an effective therapy for
paedophilia. Everything is neurochemistry. Here we have tumbled upon an insight into human neurochemistry and we will throw that door open wide, walk
the corridors and peer through the other doors. In some ways this is very exciting. In some ways this could be very frightening. I suppose we can all
agree that a cure for child molesters that is more humane than chemical or actual castration, or institutionalization, is desirable. But there is much
less likelihood of consensus on a "cure" for homosexuality for example. Simply because there won't be a consensus on whether or not it is a
pathological condition in the first place, right?
Oh brave new world!
|
|
|
Maya
Hazard to Others
Posts: 263
Registered: 3-10-2006
Location: Mercury
Member Is Offline
Mood: molten
|
|
One-Eyed Guy Wrote:
<<<< In RP there is a pH gradient and the individual peptides fall off the stationary phase one by one as the pH changes >>>>
You're starting to take a walk on the wild side here.
In RP there is a Non-polar to Polar gradient NOT a pH gradient. Typically Acetonitrile in water going from 10% to as high as much as 90-100%
acetonitrile.
Surprised you would invest so much and not know this.
 
[Edited on 12-1-2007 by Maya]
\"Prefiero ser yo extranjero en otras patrias, a serlo en la mia\"
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
@Maya I am talking about quad RP, with one of the compenents being an aqueous high concentration of (usually ammonium) salt. Of course there is a pH
gradient and it is the pH gradient that knocks off the peptides (or amino acids) one by one with such high selectivity from their perches on C4 to C18
stationary phases.
|
|
|
Maya
Hazard to Others
Posts: 263
Registered: 3-10-2006
Location: Mercury
Member Is Offline
Mood: molten
|
|
Sounds like you're doing ion exchange chromatography instead.
I've never heard of Quad Reverse-Phase Chromatography, and I've done my share of RP.
In RP it is the increasing non polarity that knocks them off their perches. in ion exchange it is increasing ion concentrations.
You gotta pick one column c14 or c18, or are you saying you have them in tandem?
\"Prefiero ser yo extranjero en otras patrias, a serlo en la mia\"
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
For two component systems such as H20/MeCN your description is spot on.
And in fact the extreme examples I was thinking of (seperation of human vs rabbit insulin which differ only by a single methylene) were such systems.
I am hunting around on ht HDD for a description of a 4-component (hence, quad) RP procedure, with a pH gradient, and I will post it if and when I find
it. If I can't I will own up to having misspoken. Fair enough?
I'd best know what I'm about with this as I really have dropped all that $$$ into five Waters 600E analytical systems, two PrepLC 4000 systems, a 650E
Advanced Protein Purification System, a pile of 486, and 490E UV detectors, a 994 PDA, and Millenium32 workstations to run it all on IEEE-488 buses.
Not new but in good shape. Spares are for redundancy and for cannibalizing for parts in instances where Waters no longer supports the model (as with
the 490Es).
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
No the only thing I use ion exchange chromatorgraphy for is desalting after global deprotection and before HPLC. Done on CMC.
Have you got DryLab?
If so look for RP Gradient/pH as they have examples of this technique.
No I was not talking about two columns in tandem, just giving a useful range of bonded phases.
[Edited on 12-1-2007 by Sauron]
|
|
|
Maya
Hazard to Others
Posts: 263
Registered: 3-10-2006
Location: Mercury
Member Is Offline
Mood: molten
|
|
Gotcha , 4 component liquid RP is a better descriptor.
<<< Have you got DryLab? >>>
No, I haven't worked on HPLC in > 10 years. However we are working on a synthetic D-amino acid peptide, 10 AA, that we will be making 20 construct
variants of pretty soon so we may invest in a new state of the art system soon.
Thats alota green to drop into satisfying your curiosity when there doesn't appear to be exclusivity or maybe even optimization yet.
side note , maybe we should also look into some SAR modeling sofware as well but I haven't much practical knowledge of these systems for our peptide
receptor work.
\"Prefiero ser yo extranjero en otras patrias, a serlo en la mia\"
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
Are you using Merrifield (automated synthesizer) techniques, i.e., solid phase, or classical wet lab preps?
I can't afford the former so I am planning the latter.
Also I like to see some product rather than a smudge at the bottom of a sample vial. Just a personal prejudice.
10 AAs not too bad, is it linear or cyclized?
Yes $40K a pretty penny to see go over the event horizon of the black hole of a money pit that is my hobby. But I don't have any kids, am well off,
and thus I indulge myself.
Besides I figure I might have other uses for this stuff down the road. At least that's what I keep telling myself to assuage the pain in my wallet.
[Edited on 12-1-2007 by Sauron]
|
|
|
Maya
Hazard to Others
Posts: 263
Registered: 3-10-2006
Location: Mercury
Member Is Offline
Mood: molten
|
|
So far our cost has been ~$2k a gram.
We've outsourced till now but 20 variants would be well over $35K so may be cheaper to do inhouse. if we do, we have a core that says they have a
robotized peptide synthesizer, don't know if its merrifield. Otherwise it might take me awhile if I have to do it all myself wet wise.
Linear peptide, I would imagine you end up with smudges more often on cyclization attempts
\"Prefiero ser yo extranjero en otras patrias, a serlo en la mia\"
|
|
|
Maztec
Unregistered
Posts: N/A
Registered: N/A
Member Is Offline
|
|
the mode of action of slidenafil
http://www.ch.ic.ac.uk/local/projects/p_hazel/mode2.html
synthesis of slidenafil
http://www.ch.ic.ac.uk/local/projects/p_hazel/synthesis2.htm...
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
The standard cyclizing agent for the heptapeptide, linking the Asp and Lys side chains, is DPPA (diphenyl phosphoryl azide.) Yields are rather low.
15-20% IIRC.
I have read about superior cyclizing reagents but they remain rather exotic and I have not heard of their use in this application being published.
Even DPPA does not seem commercial, it is prepared from diphenyl phosphoryl chloride and NaN3. The details are in Bodanzsky, The Practice of Peptide
Synthesis.
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
@Maztec, that's the earlier prep of sildenafil. Pfizer worked out a much better route and two of their chemists published it in one of the major
journals.
The order of steps is different.
They replaced the politically incorrect SOCl2 with CDI (carbonyl diimidazole) a peptide coupling reagent.
Other improvements I can't recall.
Both the procedure you posted and the improved Pfizer process were up on Rhodium years ago. Which is where I saw them.
|
|
|
Maya
Hazard to Others
Posts: 263
Registered: 3-10-2006
Location: Mercury
Member Is Offline
Mood: molten
|
|
You've got a His and Tryp in close proximity as well , that is unusual.
wonder how much of the low yield is due to stereoisomeric strain and how much is due to non-specific rxns
did you get u2?
\"Prefiero ser yo extranjero en otras patrias, a serlo en la mia\"
|
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
Sorry @Maya no u2 here yet.
I don't know why the low yield.
The His is Bom protected, the Trp is N-formyl. These are knocked off just prior to cyclizing.
|
|
|
Jdurg
Hazard to Others
Posts: 220
Registered: 10-6-2006
Location: Connecticut, USA
Member Is Offline
Mood: No Mood
|
|
Guys, don't forget that Sildenafil isn't a compound that only works on the male penis. It works throughout the entire body. The fact that the penis
becomes erect is simply a beneficial side effect. If you don't have erectile dysfunction and take Sildenafil you may still experience some of the
effects of the drug which may not be too good for you. Sadly, people don't bother paying attention to how a drug works. They just believe what they
read in the media and this leads to a lot of tragic results.
I really wish I could go into more detail about Sildenafil and it's other uses, but the NDA I signed when I became employed by Pfizer PGRD prevents me
from saying anything further. The only thing I can say is that Sildenafil is being tested on more than just penis problems.
\"A real fart is beefy, has a density greater than or equal to the air surrounding it, consists of the unmistakable scent of broccoli, and usually
requires wiping afterwards.\"
http://maddox.xmission.com. |
|
|
Sauron
International Hazard
Posts: 5351
Registered: 22-12-2006
Location: Barad-Dur, Mordor
Member Is Offline
Mood: metastable
|
|
If I recall the trials during which the "payday" side effect was noted, was for a beta-adrenergic.
Some other side effects are well known: color shift in vision (blue-green shift).
Many of the knockoffs are notorious for headaches, perhaps their QC sucks. Personally I'd stick to the real McCoy. And then only if it is needed.
There is a famous contraindication: do not combine with organic nirites/nitrates. One vasodilator potentiating the other. Can be fatal.
|
|
|
Sandmeyer
National Hazard
Posts: 784
Registered: 9-1-2005
Location: Internet
Member Is Offline
Mood: abbastanza bene
|
|
| Quote: | Originally posted by Sauron
There is now a true human aphrodisiac, one that directly stimulates the libido and it is effective on both men and women. |
True, it's called GHB...
|
|
|
| Pages:
1
2
3 |
![[*]](images/xpblue/default_icon.gif){kind=icon}
