The Half Decent Pharmaceutical Chemistry Blog

Tonight, we tell the amazing story of how you sit in front of a computer and, out of nowhere, a new drug comes out.

Hello and welcome! I think some of you have probably put up an annoyed and disgusted expression reading what drug I’m going to discuss tonight: last year, I tackled H₂-antagonists both pharmacologically (as a class of molecules) and synthetically (in the sense that the synthesis of Cimetidine has been already described). So, you might be led to believe I’ve either run out of ideas or developed some kind of H₂-blockers fetishism. Well, I am actually pretty fond of all the drugs which treats gastrointestinal diseases as they were the theme of my very first lecture on pharmacology and, subsequently, the first thing I studied. Luckily, my intestine and I have always had a wonderful relationship: I don’t stress it and it keeps working efficiently and quietly.
Sure this remains an interesting (and much underestimated) subject of study, but the main reason why I’ve chosen Ranitidine is that it gives me the opportunity to talk about an even cooler aspect of pharmaceutical chemistry which, weirdly, has never covered: QSAR.

These days, nearly every new molecule which may eventually manage to end up as a marketable drug is discovered through one of the many computer-assisted drug design techniques. The Romantic (maverick) scientist who finds some nasty mould from which one can obtain a revolutionary antibiotic has now been replaced with a nerdy geek, who sits in front of an insanely powerful computer in a dark room. Actually, I have always mixed feelings when I think about these guys: most of them prove to be complete idiots when you try to talk with them, but there are brilliant scientists who, thanks to their skills, (will) succeed at solving problems that seems impossible if considered solely from a traditional point of view.
What’s more, because they work at a computer, they are able to visit my blog when want to take a break, so, I must be more polite when refer to them.

QSAR is one of so-called correlative techniques you can use to discover new molecules. The acronym stands for Quantitative Structure-Activity Relationship: self-explanatory, isn’t it? It’s defined correlative comes from the assumption that there is a correlation between the biological activity and chemical-physical properties. This relationship is mathematically (and, therefore, quantitatively) determined as follows: you first define some descriptors (x), that quantify well-known chemical physical properties. These descriptors are applied to a number (n) of molecules with known activity (y). With these two variables (x and y) one creates a matrix and, through regression analysis (least squares) yield a model to calculate the structure-activity relationship.
In a nutshell, you have to work out  the a’s in the equation: y = a₁x₁ + a₂x₂ +…+ a_nx_n.

If you haven’t fallen asleep with my quick lecture of mathematics, that’s great, because you can now see how all this monumental amount of calculations comes to play in the drug-design process. You take a basic, structural backbone and choose two positions. Then, you start to size which substituents would be the best there. The aforementioned descriptors (x) generally have to do with lipophilicity, steric hindrance, electronic properties such as mesomeric and inductive effect of the substituents, etc. On the other hand, to quantify activity (y), pIC₅₀ (concentration of a drug to halve the activity of an enzyme) is often chosen.
Amazingly, this statistical approach gives one the opportunity to predict whether a descriptor would be relevant or irrelevant.
To sum up, the great thing about QSAR is that it gives us a hint on the possible activity of a molecule that hasn’t been designed yet.

You might think: “Yes (yawn),  it’s all fantastic and brilliant but what the Hell has it got to do with Ranitidine!” Well, once Cimetidine (first H₂-blocker to be clinically used to treat peptic ulcer disease, people at Glaxo got excited and asked themselves how they could possibly further improve an already superb drug. So, they set their nerdest drug-designers to work at their ultra sophisticated computers and  they came up with some interesting findings (those damn geniuses…): first, you could replace the imidazole with a furan (a dimethyl-amino-methyl-furan, to be precise); then, it was a reasonable thing to do to preserve the highly flexible, long, side chain, keeping the sulphur but changing the cyano-methylguanidine with a nitroethene-diamine. Thanks to these pure prediction made with a QSAR programme, they had invented Ranitidine, an H₂-blocker 4 to 10-times more potent than Cimetidine, 4 to 10-times less prone to bind to cytochrome P450 and longer half-life.

I’m pretty sure they were listening to an early eighties’ (the year Ranitidine was discovered) big hit such as “Another Brick in The Wall” by Pink Floyd as it would perfectly match with the image of a dark room (only lit by monitors) with many people staring at a computer, in the office of a big, evil, pharmaceutical company. And the Pink Floyd were pioneers in the use of electronics in rock music.

The synthesis of this…synthetic drug starts with an amazing Mannich reaction to introduce the amino alkyl group, thanks to the acidic proton of furan. Thionyl chloride is chosen to get a better leaving group (instead on the primary hydroxyl) so that the flexible chain could be bound to the other end of the furan. Meanwhile, nitromethane and carbon disulfide react (in the presence of two equivalents of potassium hydroxide and dimethyl sulphate) to yield a precursor of the nitroethene-diamine, which easily reacts with the amino terminal of the chain.
Finally, a methanethiolate group is substituted with a methyl amino one by adding methylamine.
Impressive, isn’t it?