Avoiding some treacherous pockets

A week or so ago, Dr. David Price of Pfizer visited our department and gave a great talk on Maraviroc, an HIV antiretroviral drug. While the story David shared with us was unique in many ways, it did have a number of elements in common with other tour-de-force kinds of studies in medicinal chemistry. Invariably, these cases show that good chemistry is only a part of a journey to a successful drug. Chemistry is, nonetheless, a critical component of any drug discovery undertaking. We had some good fun with David, and we do look forward to seeing him again in the near future. While a lot of interesting stories can be mentioned about Maraviroc, I was particularly intrigued by David’s reference to one of the main killers of promising compounds in drug design. I refer to the infamous HERG potassium ion channel. The architecture of this channel offers a cemetery (of sorts) for aromatic compounds. The HERG liability is serious as molecules that plug this channel lead to cardiovascular side effects. David shared with me one of the papers from Pfizer that speaks to this problem:

http://www.sciencedirect.com/science/article/pii/S0960894X06006615

I started digging into this area and, after doing a bit of further research, found another great article that is foundational when it comes to HERG and liabilities associated with it. This 2002 paper by Recanatini describes the HERG pharmacophore, which is similar in its topology to a Bermuda-like triangle, wherein many promising small molecules lie. The term “pharmacophore” is often synonymous with “we do not have a crystal structure, so here is the best model we could get that is based on analysis of a series of molecules”. While it may take some time to finally see a crystal structure for this channel, it seems that if you have the right constellation of three aromatic rings in your molecule coupled with a basic nitrogen, you might be in trouble. I wonder if macrocycles have a free pass here by virtue of their geometry… I doubt it, but who knows? By the way, the Pfizer team did a great job of steering away from this dreadful triangle in their Maraviroc campaign.