The Rule of Five

AN interesting article at Derek Lowe's website regarding a rule used to evaluate potential drugs: bq. Bigger and Greasier When I was talking about chemical space the other day, I alluded to the attempts to cut it down to "druglike space" by use of rules of thumb. The most famous of these is Chris Lipinski's "Rule of Five", a summary of which can be found here. Lipinski and his Pfizer co-workers looked over a data set of drug candidates and noticed that there were some reasonably clear cutoffs for oral absorption and general cell permability. They suggested that you need: bq. 1. Fewer than five hydrogen bond donors (which can be estimated by counting the total number of OH and NH groups in the molecule.) 2. A molecular weight of less than 500. 3. A logP of less than 5 4. And fewer than 10 hydrogen-bond acceptors (estimated by the total of N and O atoms in the molecule.) bq. The "rule of five" name came from the cutoffs all being multiples of five, in case you're wondering why there are only four rules. And some more: bq. There's a recent paper by John Proudfoot at Boehringer Ingleheim (Bioorganic and Medicinal Chemistry Letter 15, 1087, for those of you playing along at home) which looks at a more comprehensive list of compounds than the original Lipinski batch. He finds that the cutoffs might be more like 470 for molecular weight and 3 for hydrogen-bond donors, but otherwise his analysis tracks Lipinski's pretty closely. (He notes that only a handful of drugs ever violate both those cutoffs simultaneously.) bq. His paper also includes a year-by-year analysis from 1937 to 1997. The only clear trend is that molecular weights have been increasing, from under 300 to the point where we're banging up right against that 500 line. Personally, the largest molecule I've ever submitted for testing weighed quite a bit more than that, but I had my reasons. It came in at exactly 747, and I couldn't resist. A fascinating look at one of the tools of pharmaceutical chemistry...