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.

Receptor binding studies of soft anticholinergic agents

“…All structures were optimized using the AM1 advanced semi-empirical quantum chemical method (39) Twenty-five descriptors were studied in our search for possible relevant parameters: molecular weight (MW); van der Waals molecular volume (V) and surface area ( S) together with the corresponding ovality (O) as a shape descriptor (40); effective van der Waals molecular volume ( V e ) and surface area ( S e ) together with the corresponding ovality (O e ) calculated with a new procedure and a slightly different van der Waals radii set (41); AM1 calculated dipole moment (D), average polarizability (α), ionization energy ( I), and heat of formation; HOMO-LUMO energies (E HOMO , E LUMO ); absolute electronegativity (χ), calculated as the negative of the average HOMO and LUMO energies, and absolute hardness (η), calculated as half the HOMO-LUMO difference; calculated log octanol-water partition coefficient (log P o/w ) using BLOGP (40), QLogP (41,42), and MLOGP (43); calculated log water solubility (log W) using BLOGW (44); AM1-calculated partial atomic charges on the quaternary nitrogen ( q N ) atom and the sp 2 carbon and oxygen atoms of the ester moiety (q C= , q O= ); the distance between the quaternary nitrogen atom and the sp 2 carbon of the ester moiety (d C-N ); and the inaccessible solid angle around these atoms (Ω C , Ω N ) as a measure of steric hindrance (45).…”

Human and Rodent Carboxylesterases: Immunorelatedness, Overlapping Substrate Specificity, Differential Sensitivity to Serine Enzyme Inhibitors, and Tumor-Related Expression

“…In rabbits, microsomal carboxylesterases are shown to interact with and regulate the secretion of acute-phase response proteins, such as C-reactive protein (Macintyre et al, 1994). Given the fact that many therapeutic agents are esters or amides, carboxylesterase-mediated hydrolysis is given an important consideration in drug designs (Graffner-Nordberg et al, 1998;Buchwald and Bodor, 1999).…”

Retrometabolism‐Based Drug Design and Targeting

“…Hydrolytic lability is also of considerable relevance for a ranking of SD candidates as it is a measure of their "softness" (metabolic stability); therefore, we undertook a quantitative structure-metabolism relationship (QSMR) study to identify a structure-based QSMR equation that is not limited to congener series [405]. In vitro human blood data was used because it represented the data of interest available in the largest number over the widest range of structures under comparable experimental conditions.…”