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April 9, 2010
Dundee's NMT Inhibitors for Sleeping Sickness: An Update
I've had some follow-up with the people at Dundee who reported those compounds for sleeping sickness recently. As mentioned, one of the key points in making these a viable therapy will be brain penetration, since trypanosomes in the central nervous system are a hallmark of the most serious phase of the disease.
The group has a patent application out (WO2010026365), and you can see from it that they've been addressing this problem. Their Table 5 has blood and brain concentrations after dosing in mice, and there's a compound on it (DDD73490) with a brain/blood ratio of 6. That one, as the med-chem audience will have no trouble believing, has an N-methyl on the sulfonamide - getting NH sulfonamides into the brain is often a losing battle. And there are a number of other compounds on the list with fluorinated N-alkyl groups on the sulfonamide, which suggests that the plain N-methyl solved one problem but created another. The tables in the patent also suggest some other therapeutic areas that these NMT inhibitors could be used in, and I'm sure that these are being investigated as we speak.
Stephen Brand at Dundee tells me that they're definitely in the market for something else that can provide the "cis kink" that the sulfonamide gives their structures, so if anyone has any ideas, please feel free to suggest them. My thoughts turn to seeing if a fragment-based approach might work here - perhaps there's a ligand-efficient piece to these compounds that could be used as a new starting point to build out to something with a lower molecular weight and better properties?
Antitrypanosome compounds are never going to make anyone rich, but if they work out, they could relieve a tremendous amount of pain and suffering in the tropics. They're being developed in partnership with the Drugs for Neglected Diseases Initiative, and the group is also looking into partnering opportunities to go after Chagas Disease. That'll be harder, but well worth a look.
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