Designing Opioid-TRIs for Chronic Pain
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.
Subject of Next Post: Poll
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
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
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.
Drug Space: The Reality 02
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.
Drug Space: The Reality 01
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.
Finicky SAR: 01
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.
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.
How Drugs are Discovered: 01
This is a spoof series made by a “retired” blogger known as PharmaGiles. It was collected and compiled by someone I know..
Please download the pdf, and have a laugh.. use the “scroll” setting on slide to a quick glance, and the “slide” setting (with Fullscreen) for maximum effect.
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.
or try this link..
Pharma Spoof
Family Resemblances: Atypical Anti-Psychotics 01
One of the most popular justification for the high cost of developing new drugs stems from the belief that expensive research and testing is necessary to develop newer and better drugs. The corollary to that concept is that such research involves developing new and innovative structures, finding better pharmacophores and generally developing therapeutically superior ‘druggable’ compounds.
I plan to examine this belief in a series on this blog. There will be other series devoted to other issues such as new uses of old drugs, dissection of popular hypotheses of chronic diseases and case studies of drug discovery etc.
So let us start by considering a series of popular and controversial drugs, namely tricyclic atypical anti-psychotics.
The first typical anti-psychotic, chlorpromazine, was itself a tricyclic derived from the antihistamine (H1) antagonist pharmacophore.
Clozapine was discovered in the 1950s, and a case study of it’s discovery will be the subject of a future post. In any case, it was first marketed in Europe in the early 1970s, where it’s peculiar side-effects (agranulocytosis) were quickly discovered. After being withdrawn and reintroduced, it is still the ‘gold’ standard for treatment resistant schizophrenia.
There have been many attempts to discover a drug with the therapeutic efficacy of Clozapine, but without its haematological side-effects. Given that Clozapine is still the ‘gold standard’ for efficacy in schizophrenia, we have not succeeded. However a number of financially successful, but less efficacious drugs based on Clozapine have been developed over the years. These drugs include compounds such as Olanzapine (Zyprexa) and Quetiapine (Seroquel). Many of these drugs have been in limelight under less than favorable circumstances, such as promotion for non-approved uses including treatment of strong-willed children, nursing home residents with dementia etc (could put lots of links, but you can google the subject matter). The irresponsible promotion of these drugs has resulted in severe image problems for the companies involved in their marketing.
try this link..Clozapine-analogues-01 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.
However, the marketing shenanigans of Eli Lilly and AstraZeneca are not the subject matter of this post. The real questions are much more troubling, namely: Why have we not discovered a safer Clozapine and why are less effective and structurally similar drugs hailed as the fruits of large R&D programs?
Given that Clozapine has a very different receptor binding profile than Olanzapine or Quetiapine (the subject of yet another post), why can we not translate our understanding about the role of dopamine receptor subtypes and concurrent effects on other neurotransmitter systems into better anti-psychotic drugs. Clearly, the market for such a compound is quite large as it the diversity of technology and assays to synthesize and assay such ligands.
So what is it?
