| METHOD |
A novel structural parameter can predict the oral bioavailability of a drug--that is, the degree to which it becomes systemically available when taken by mouth. A research team finds that compounds with good oral bioavailability tend to have reduced molecular flexibility, as measured by the number of freely rotatable bonds. The paper highlights "the importance of rotatable bonds in determining oral bioavailability, independent of molecular weight. Low molecular weight has generally been considered a prerequisite for "druglike" properties. "Our analysis opens the possibility that new drugs can be found more easily in the high-molecular-weight range, provided the number of rotatable bonds is minimized." For the past few years, the "rule of five" developed by senior research fellow Christopher A. Lipinski (now retired) and colleagues at Pfizer in Groton, Conn., has been the standard approach for predicting oral bioavailability from structure data. "The number five or a multiple occurs in all of the cutoff parameters," Lipinski explains, "but there are only four rules--involving molecular weight, number of hydrogen bond donors and acceptors, and lipophilicity." The new rotatable-bond rule complements the rule of five. Authors discovered the parameter by studying 1,100 compounds in Co.'s archive. About 65% of fairly rigid compounds in the collection (those with seven or fewer rotatable bonds) exhibited good-to-excellent oral bioavailability, independent of molecular weight. In contrast, more than 75% of floppy compounds (those with more than 10 rotatable bonds) had poor oral bioavailability. Compounds of intermediate rigidity fell somewhere in between. The scientists caution that data on oral bioavailability in rats were used in the study, so the results may not correspond exactly to human oral bioavailabilities |
| UPDATE | 06.02 |
| AUTHOR | This data is not available for free |
| LITERATURE REF. | This data is not available for free |
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