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Most Requested Journal Articles 2002-Chemistry and Related
 Following is one of the documents most requested by researchers using CAS electronic products.
CAPLUS COPYRIGHT 2003 ACS
Oral bioavailability measurements in rats for over 1100 drug candidates studied at Smith-Kline Beecham Pharmaceuticals (now Glaxo Smith-Kline) have allowed us to analyze the relative importance of mol. properties considered to influence that drug property. Reduced mol. flexibility, as measured by the no. of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of mol. wt. That on av. both the no. of rotatable bonds and polar surface area or hydrogen bond count tend to increase with mol. wt. may in part explain the success of the mol. wt. parameter in predicting oral bioavailability. The commonly applied mol. wt. cutoff at 500 does not itself significantly sep. compds. with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compds. which meet only the 2 criteria of (1) 10 or fewer rotatable bonds and (2) polar surface area .ltoreq.140 .ANG.2 (or 12 or fewer H-bond donors and acceptors) will have a high probability of good oral bioavailability in the rat. Data sets for the artificial membrane permeation rate and for clearance in the rat were also examd. Reduced polar surface area correlates better with increased permeation rate than does lipophilicity (C log P), and increased rotatable bond count has a neg. effect on the permeation rate. A threshold permeation rate is a prerequisite of oral bioavailability. The rotatable bond count does not correlate with the data examd. here for the in vivo clearance rate in the rat. View the full-text pdf document from the American Chemical Society, a participating ChemPort publisher. Updated 5/4/2007 9:24:07 AM
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