Copycat drugs

 Credit Jiri Sliva

Levitra is a close Viagra knock-off and there is little difference between the two for the patient. “Money wasted on developing yet another version of the erection pill could have been put into malaria research instead.” And so on.

I am not a fan of Big Pharma but I would like to point out that the misery of the Third World was not caused by the lack of drugs or by their high prices - the root problems have to do more with awful governments and wars. But if most patients there cannot pay for the new antimalarials / HIV inhibitors / tuberculostatics, the research interest will get re-directed elsewhere and one can hardly blame the industry for that.  (Another complication is that even if the drugs are provided for free, it is hard to get these patients to take their medications in a disciplined manner for the prescribed period of time - and hence the multidrug resistance emerges soon)

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Sepracor business plan used to be entirely based on patent-busting; Sepracor was scorned for it by many people in the industry. Yet this kind of ”bottom-feeding” research saved some good drugs from oblivion - drugs that would not be introduced into US otherwise. As a result, a next generation of drugs appeared in previously stagnant fields. (Antihistaminics, sleep meds.) 

A competition from me-too drugs produces pressure that pushes the innovation - without it, companies selling popular drugs are in no hurry developing their more advanced follow-on candidates if their established drug is doing fine. 

A late-comer drug needs to offer some demonstrable advantage over the more established ones. The me-too drug can for example have a different pharmacology from the original drug – whether this was a part of the design or just a coincidence. (The drug distribution, metabolism, drug-drug interactions and side-effect profile are notoriously hard to predict: a small change in the structure can have an important effect which might not be apparent until the testing is done in patients). The main reasons for doing the me-too medchem research is that it is a lot easier: Developing a new structural class from a low-potency screening hit can take years and there is no guarantee that this optimization will ever produce a drug candidate. Starting with a proven competitor’s compound and modifying it in few places greatly shortens the development time and improves the chances of success. 

It is just impossible to exhaust all possibilities inherent in a class of molecules. The chemists and biologists in the team that discovered the original drug must have made choices at numerous points of the project- when they picked the directions they thought were worth pursuing. Their project had deadlines, it was influenced by personal experience and bias.  Independent re-visiting the original data and premises with the hindsight knowledge of the clinical performance and with a competitive mindset can lead to surprises, and eventually to an improved drug candidate.  

There is also a natural tendency of compounds coming out from different groups to converge:  It is a common practice in the industry to re-synthesize and test the published compounds. The added insight from their testing (especially when combined with the X-ray crystallography) can quickly close the gap between the competing groups. This can also produce a resemblance of a me-too approach.

Soliciting advice on diazomethane

 Credit: Jiri Sliva

I have been doing Arndt-Eistert homologation (example: OrgSyn 79, p.154, 2002) so I needed pure anhydrous diazomethane solution. I made diazomethane from nitrosomethyl urea (NMU) and to avoid the distillation, I transfered diazomethane from my KOH-dried diazomethane solution in toluene by passing a stream of Ar through it (at R.T. for 30 min) and condensing the liberated dry Ar-diluted diazomethane gas directly into the reaction mixture cooled to -78C. (I heard of this alternative of diazomethane solution distillation from Rapoport group – and it worked, though I cannot recomend doing this kind of gas transfer on large scale because diazomethane is so nasty and toxic.)

I have only a limited experimental experience with diazomethane. There is plenty literature on the subject. But I would like to ask you about your personal perspective: What is you favorite method of making high-purity dry diazomethane solutions (that can be used for sensitive applications such as Arndt-Eistert)? 

One reason why I am asking this is that it apears to me that all the commonly used precursors of diazomethane have some problems associated with their use: Diazald needs a presence of alcohol (preferably a high-boiling one) or a phase-transfer catalyst to work with aqueous hydroxide and the produced diazomethane solution should be distilled to remove the sideproducts. MNNG is highly toxic and difficult to buy nowadays. NMU is expensive, explosive, very carcinogenic and the NMU-produced diazomethane solution contains trace of methylamine. So I would be delighted to learn what you have tried and liked.

The other reason is that I have one rather simple-minded idea – that I would like to try, to see if it works –  for a method of preparing contaminant-free anhydrous diazomethane solution without the risky distillation step. I would like to know if you think it is a worthwhile use of lab time, if you think a new method is even needed - a method that would be convenient and work with benign commercial reagents.