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Designing Opioid-TRIs for Chronic Pain

January 18, 2010

Another product of the patented mediocrity machine. Enjoy!

The idea here is a new class of drugs to treat moderate to severe pain, without causing excess sedation and elevating mood. I have skipped representations of chirality, as it makes it easier to visualize.

Try this link.. Mixed-Opioid-TRIs Local Link

or

If you cannot see the embedded Scribd document properly, please change the Scribd window setting to “scroll” fom “slide” in the drop down menu of the Scribd embedded box. I am trying to fix the problem.

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Subject of Next Post: Poll

January 18, 2010

I will write on all three, but your input will help me decide on the order of writing. As you probably understand, these posts cannot be edited within a few hours, though I have written up most of the material. A bi-weekly or weekly posting intensity works well for this type of blog.

I have a feeling that MBAs will vote for option number 3.

The Mediocrity Machine

January 11, 2010

The Patented Mediocrity Machine is my brain coming up with new ideas, when I am bored.

I have two kinds of ideas:

The truly original ideas that do not come often (and will not write on this blog)

and

Mediocre but still useful ideas that are often overlooked, and I have tons of them.

I am posting my mediocre ideas because the standard of ideas in the MBA and lawyer infested pharma sector is so much worser. It is also an easy way to put ideas in the public domain in a manner that bypasses journals and a lot of innovation killing bullshit. Ideally I would like to make money from some of my ideas and I would have preferred to go via traditional channels. But in a world based on whom you know, and which lab you did your Ph.D in (you know.. the opposite of meritocracy) it is hard. It certainly does not help that even with a patent, a larger company can outlawyer you.

So this is my response…

Designing TRIs: Adventures in Mediocrity

January 10, 2010

I had a look at the pharmacophore requirements of Triple Reuptake Inhibitors (TRIs) and thought that some older drugs could be spruced up to act as TRIs. The reasons why I do this are here.

Tranylcypromine is an old monoamine oxidase inhibitor.

Methylphenidate and Pemoline are combined D & NA reuptake inhibitors used for ADHD

DOV 216,303 and GSK 372,475 are investigational TRIs (S,NA and D).

Why not combine the pharmacophores?

Try this link..Designing-Super-Antidepressants-01 Local Link

or

If you cannot see the embedded Scribd document properly, please change the Scribd window setting to “scroll” fom “slide” in the drop down menu of the Scribd embedded box. I am trying to fix the problem.

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Drug Space: The Reality 02

January 9, 2010

Another post that shows how tiny drug space can often be, and how most innovation is about finding structures that are patent-proof and not unique or truly novel.

Triple reuptake inhibitors (TRI) are a “new” class of drugs which simultaneously inhibit serotonin, norepinephrine and dopamine transporters. They have real and innovative therapeutic potential in treatment of moderate to severe depression and obesity, and seem to lack the side effects (sexual dysfunction and weight gain) seen with SSRIs. Moreover they seem to start acting faster than SSRIs.

While the concept of TRIs is not a new one, the stigma of having a drug molecule look like cocaine or amphetamine had long made it an unsaleable concept in the field of drug development. The pseudoscience on drugs that modulate the effects of dopamine performed during the 1980s and 1990s, to support the ‘war on drugs’ , was certainly not helpful.

In any case, TRIs are being now developed by a number of companies, however the first three to unergo extensive testing in large clinical trials look a lot like each other (see Red Box). I have removed chiral information from the molecules to help you see the issue better. Note their resemblance to the older antidepressant Bupropion and the newer appetite suppressant Sibutramine (see Black Box). SEP-225289 is a primary amine version of Sibutramine (extra methyl groups on Sibutramine highlighted with green circles).

Try this link..Triple-reuptake-inhibitors Local link

or

If you cannot see the embedded Scribd document properly, please change the Scribd window setting to “scroll” fom “slide” in the drop down menu of the Scribd embedded box. I am trying to fix the problem.

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Drug Space: The Reality 01

January 7, 2010

Sometimes, a picture or two can say a thousand words. Note that all drugs in both slides are still commercially available and have different pharmacological effects. In many cases, they were true innovations in their therapeutic areas.

Try this link.. H1-and-oxetines Local link

or

If you cannot see the Scribd document properly, please change the Scribd setting to “scroll” fom “slide” in the drop down menu of the Scribd embedded box. I am trying to fix the problem.

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Finicky SAR: 01

January 7, 2010

Certain scaffolds are blessed, or cursed, with extremely finicky SAR. Consider the scaffold in the box, which can with very little modification give you amoxapine (antidepressant), loxapine (typical anti-psychotic?), clozapine (the 1st atypical anti-psychotic), olanzapine (another atypical anti-psychotic) and quetiapine (still another anti-psychotic).

Try this link..Clozapine-analogues-02 Local Link

or

If you cannot see the Scribd document properly, please change the Scribd setting to “scroll” fom “slide” in the drop down menu of the Scribd embedded box. I am trying to fix the problem.

View this document on Scribd

Amoxapine blocks the reuptake of norepinephrine (strong) and serotonin (weak), and one of its metabolites is a dopamine antagonist.

Loxapine has high affinity for multiple dopamine receptor subtypes (D1, D2, D4) and some activity at 5-HT2 receptors.

Clozapine affects the D4 receptor subtype without significant activity at the D2 receptor, but has measurable activity at multiple 5-HT receptors (including 5HT-2)

Olanzapine has high affinity for both 5HT-2 and D2 receptors.

Quetiapine has high affinity for the D2, 5-HT-2 and some alpha-adrenergic receptors.

Activity towards muscarinic and H1 receptors is also found in some of the above drugs depending on whom you ask.

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