Quantitative Structure−Metabolism Relationships:  Steric and Nonsteric Effects in the Enzymatic Hydrolysis of Noncongener Carboxylic Esters

• Published in: Journal of medicinal chemistry 1999-12, Vol.42 (25), p.5160-5168
• Main Authors: Buchwald, Peter, Bodor, Nicholas
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Carboxylic Acids - metabolism; Carboxylic Ester Hydrolases - metabolism; Esters - metabolism; General pharmacology; Half-Life; Humans; Hydrolysis; Medical sciences; Pharmacokinetics; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990145k

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.