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Designing a New Drug: Ideas for a Drug Design Project

I like the idea of linking an amphetamine to another amphetamine. I was messing around on ChemSketch and thought about this: d-amphetamine and d-methylphenidate linked by leucine. I'm not too familiar with my drug metabolism (our textbook is kind of confusing), but I thought that the leucine would be able to be cleaved from the amphetamine and the leucine would be cleaved from the ester group on methylphenidate somewhere along the way. Would this work?

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knockout_mice said:
Reuptake inhibitors block the activity of releasing agents, aren't they?
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*facepalm* I didn't even think about that. I've heard that low doses of methylphenidate with amphetamine (or was it the other way around?) have a synergistic effect, but this would leave a 1:1 ratio, so it wouldn't work. I also realized that if the leucine is cleaved from the methylphenidate, it would become ritalinic acid, which apparently is an inactive metabolite. So back to the drawing board...

So I'm trying to think of another way to link the two maybe, or maybe find another drug to link to amphetamine. What could be some other linker molecules that would make it to the liver other than amino acids (perhaps with structures similar to amino acids)? Could an analog of leucine be able to be cleaved like lysine is cleaved from amphetamine in Vyvanse? If so, I figured I could try linking amphetamine and modafinil with a leucine analog.

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I figured it would automatically be a prolonged release prodrug, and also since modafinil has a lower abuse potential, it might be an ideal drug with a lower recreational value than even Vyvanse. Even though modafinil acts as a DRI, I have read that low doses of modafinil with amphetamine are synergistic. If there's a 1:1 ratio of amphetamine and modafinil, then it would be like 30mg of amphetamine with 30mg of modafinil, which doesn't seem like it would be a high enough dose of modafinil to "cancel out" the amphetamine.

If modafinil is not an ideal drug to link, what other stimulants would work (with a primary amine)? I've looked through many of the PIHKAL phenethylamine derivatives on wikipedia but it seems that most of them have hallucinogenic effects like MDMA. I'm still looking for some with mostly stimulant effects. Also, most of the other stimulants I've found are DRIs, which would not be ideal. I've also looked through substituted amphetamines on wikipedia, but it's hard to tell which ones are better.


You all have no idea how much appreciate all the help and feedback you all have given so far. =D I owe you guys big time, hahaha.
 
What advantage do you think a bifunctional prodrug will have over administering equal ratios of both drugs together in one pill?
 
endotropic said:
What advantage do you think a bifunctional prodrug will have over administering equal ratios of both drugs together in one pill?
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Good question. My idea is that maybe if I can combine amphetamine with a drug that aids in concentration and alertness (and a has lower abuse potential possibly), the two drug would have some sort of synergistic or more "well-rounded" effect. Kind of like the mixed amphetamine salts idea with Adderall. I also thought it would be a more creative idea, but it might not be best. I'm still open to any suggestions or criticism though, I'd rather hear criticism here than from my professor. ;)
 
dillingerESCplan said:
Good question. My idea is that maybe if I can combine amphetamine with a drug that aids in concentration and alertness (and a has lower abuse potential possibly), the two drug would have some sort of synergistic or more "well-rounded" effect. Kind of like the mixed amphetamine salts idea with Adderall. I also thought it would be a more creative idea, but it might not be best. I'm still open to any suggestions or criticism though, I'd rather hear criticism here than from my professor. ;)
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That still doesn't distinguish your new drug from a pill that combines amphetamine and modafinil without any linker. I'm not saying the prodrug idea doesn't have any merit, just that you should be prepared to discuss what benefits that approach has compared to the two free drugs in one pill.
 
I get what you're saying now. I have come up with a few better ideas. I'm just trying to think of one other thing to add with either of these.

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So the one on the left is amphetamine bonded to tyrosine. This idea seems a bit too similar to Vyvanse, but the idea is that the tyrosine that is cleaved will also play a role in making the amphetamine function better. While high doses of tyrosine with amphetamine could lead to bad side effects, the small amount of tyrosine would help restore and maintain dopamine and norepinepherine levels. This could lead to the drug working for a longer time without issues involving tolerance. This seems like it's just a copy of Vyvanse, which is why I'd like to think of something else creative to go along with it. I'm thinking about maybe also having a substituted amphetamine (like 4-FA) with the tyrosine as well; it would be like a mix of the two.

On the right side is a [(2-sulfo)-9-fluorenylmethoxycarbonyl]-3 derivative of amphetamine. I found it while reading this review paper on prodrugs for amines. It states:
Simple N-acyl prodrugs in which slow cleavage is desirable are the [(2-sulfo)-9-fluorenylmethoxycarbonyl]-3 derivatives of glucose lowering drugs like insulin [26] (4, R=H) and exendin-4 [27]. These prodrugs have the advantage of delivering the drugs slowly to the systemic circulation reducing the risk of hypoglycaemia.
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I'm unable to find out how "slow" this delivery is, but it seems like an interesting idea. Anyone familiar with this?
 
I've already turned in my project, but I'll have to check out that link. It seems pretty interesting. I got back my grade and I got a 97 on the project and aced the final this morning, so that's an A. :) Now I've gotta ace my physics and human genetics exams coming up... 8( Hopefully I'll be able to pull these off without getting amphetamine psychosis. hahaha

Thanks again for the feedback and constructive criticism guys, it helped much more than you'd think. Well I've got to get back to studying now, wish me luck.
 
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