title: Quantitative structure-metabolism relationships: steric and nonsteric effects in the enzymatic hydrolysis of noncongener carboxylic esters.
abstract: An attempt to quantitatively describe human blood in vitro hydrolysis data for more than 80 compounds belonging to seven different noncongener series of ester-containing drugs is presented. A parameter not yet explored in pharmaceutical studies, the inaccessible solid angle Omega(h), calculated around different atoms was used as a measure of steric hindrance, and the steric hindrance around the carbonyl sp(2) oxygen (Omega(h)(O=)) proved the most relevant parameter. The obtained final equation, log t(1/2) = -3.805 + 0.172Omega(h)(O=) - 10.146q(C=) + 0.112QLogP, also includes the AM1-calculated charge on the carbonyl carbon (q(C=)) and a calculated log octanol-water partition coefficient (QLogP) as parameters and accounts for 80% of the variability in the log half-lives of 67 compounds. A number of structures are still mispredicted, but the equation agrees very well with a recently proposed mechanism for hydrolysis by carboxylesterases. The model, with a predictive power tested here on three unrelated structures, should be useful in estimating approximate rates of hydrolysis for prodrug or soft drug candidates ahead of their synthesis.
authors.affiliation: Center for Drug Discovery, University of Florida, Health Science Center, P.O. Box 100497, Gainesville, Florida 32610-0497, USA.
authors.forename: P
authors.initials: P
authors.lastname: Buchwald
authors.forename: N
authors.initials: N
authors.lastname: Bodor
mesh_terms: D002264:Carboxylic Acids / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D004952:Esters / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D010599:Pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D004952:Esters; D002265:Carboxylic Ester Hydrolases