Quantitative structure-metabolism relationships: Steric and nonsteric effects in the enzymatic hydrolysis of noncongener carboxylic esters

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 pha rmaceutical studies, the inaccessible solid angle Omega(h), calculated arou nd different atoms was used as a measure of steric hindrance, and the steri c 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 .172 Omega(h)(O=) - 10.146q(C=) + 0.112QLogP, also includes the AM1-calcula ted charge on the carbonyl carbon (q(C=)) and a calculated log octanol-wate r partition coefficient (QLogP) as parameters. and accounts for 80% of the variability in the log half-lives of 67 compounds. A number of structures a re still mispredicted, but the equation agrees very well with a recently pr oposed mechanism for hydrolysis by carboxylesterases. The model, with a pre dictive power tested here on three unrelated structures, should be useful i n estimating approximate rates of hydrolysis for prodrug or soft drug candi dates ahead of their synthesis.