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 Ω(h), calculated around different atoms was used as a measure of steric hindrance, and the steric hindrance around the carbonyl sp2 oxygen (Ω(h)(O=)) proved the most relevant parameter. The obtained final equation, log t(1/2) = -3.805 + 0.172Ω(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.