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Cardiovascular Disease

Renin, Wherefore Art Thou, Renin?

I notice that the first marketed renin inhibitor seems to be doing fairly well. That’s an interesting phrase, “first marketed renin inhibitor”. . .
This is a good example of what drug discovery can be like. Renin is a fine drug target – it’s been known for a long time as a key component of blood pressure regulation, and that’s a condition affecting a huge market whose treatment provides a real medical benefit. What more do you want?
OK, let’s make it even more attractive. It’s not that hard to set up a renin assay, and the protein is well-studied. The counterscreens and secondary assays are not a problem; hypertension is fairly well understood. And if you screen for renin inhibitors, you generally find chemical matter to start off with, too. Protease inhibitors vary quite a bit in their drug-likeness, but they’re certainly not impossible on the face of them.
But even after all this, I would not like to be asked to count how many renin inhibitors have been reported over the years, never to be seen again. The first reports I can find go back to the early 1980s. Given the lead time for these things, I can safely assume that these compounds were being made around the time I went the my high school Junior Prom (theme: “Saturday Night Fever”, natch – it was 1978, after all). And here we are in 2007, and the first one has finally made it to market. It wasn’t easy, either – the compound was left for dead years ago, and was only kept going by some ex-Novartis people who started their own company and licensed the compound back to Novartis when it finally made it through the rough spots.
So, what’s the problem? Many compounds have been done in by poor behavior in living models (distribution, absorption, and so on). Getting oral bioavailability in this area has been a lot harder than anyone thought, and even the current drug is no great winner in that category. Projects start and stop, difficulties occur, and the years go by. And other mechanisms for going after hypertension have, of course, come to market, starting with the ACE inhibitors (which come from roughly the same disco era as the first run of renin compounds). They took the gigantic market that an early-1980s renin inhibitor would have had, but even so, I don’t think a year has gone by since that someone in the industry hasn’t been working on one. (There’s still room to think that a renin compound would have a better profile than the existing drugs, though). And here we are: 2007. A sobering thought, that is.

4 comments on “Renin, Wherefore Art Thou, Renin?”

  1. Grubbs the cat says:

    this example makes me laurgh considering the timelines set these days for lead optimisation projects 😉
    obviously, one has to differenciate targets, special targets and very special targets…

  2. I heard Claude Cohen, the main inventor of Aliskiren/Tecturna, talk at a SBDD conference recently. Beautiful example of SBDD, and one of the early examples in which modeling played a fortuitous role.
    NRDD had a nice writeup on antihypertensive therapies recently in which they say that investment in the development of new antihypertensives has been declining, as companies look at combining old therapies.
    doi:10.1038/nrd2354

  3. peej says:

    Actually, the drug isnt really doing very well in a commercial sense…. its hard to figure out what advantage it would have over existing ACE or ARB drugs, and the combination could potentially be somewhat risky by causing significant hyperkalemia in the setting of decreased renal function. Its a cool compound, but doesnt have a whole lotta utility. Novartis has a full marketing machine behind it (they had a lot of down time with their DPP delay), so they are making a valiant effort, though.

  4. Jigar Desai says:

    Dear Derek
    The real problem faced by the pharma industry recently developing Renin inhibitors is not Chemistry or Invitro Biology but to choose the right animal model for invivo study which could be translet it to human at end. dTGR is model used by various company but not a cost effective. May be proper animal model is required for screening NCEs.

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