By identifying every pair of molecules that differ only by a particular, well-defined, structural transformation in a database of measured properties and computing the corresponding change in property, we obtain an overview of the effect that structural change has upon the property and set an expectation for what will happen when that transformation is applied elsewhere. The mean change indicates the expected magnitude of the change in the property and the number of cases in which the property increases give the probability that the structural transformation will cause the property to increase. Outliers indicate potential ways of avoiding the general trend. Comparing to changes in lipophilicity highlights structural transformations that have unusual effects, some of which can be explained by conformational changes. In this paper, we focus upon the effects on aqueous solubility, plasma protein binding and oral exposure of adding substituents to aromatic rings and methylating heteroatoms.

Partition coefficients were measured for 47 compounds in the hexadecane/water ( P hxd) and 1-octanol/water ( P oct) systems. Some types of hydrogen bond acceptor presented by these compounds to the partitioning systems are not well represented in the literature of alkane/water partitioning. The difference, DeltalogP, between logP oct and logP hxd is a measure of the hydrogen bonding potential of a molecule and is identified as a target for predictive modeling. Minimized molecular electrostatic potential ( V min) was shown to be an effective predictor of the contribution of hydrogen bond acceptors to DeltalogP. Carbonyl oxygen atoms were found to be stronger hydrogen bond acceptors for their electrostatic potential than heteroaromatic nitrogen or oxygen bound to hypervalent sulfur or nitrogen. Values of V min calculated for hydrogen-bonded complexes were used to explore polarization effects. Predicted logP hxd and DeltalogP were shown to be more effective than logP oct for modeling brain penetration for a data set of 18 compounds.

Comparison of the human plasma protein binding data for a variety of drug discovery compounds indicates that compounds tend to be slightly more bound to human plasma proteins, than compared to plasma proteins from rats, dogs or mice.

N-Acyl-beta-sultams are time dependent irreversible active site directed inhibitors of elastase. The rate of inactivation is first order with respect to beta-sultam concentration and the second order rate constants show a similar dependence on pH to that for the hydrolysis of a peptide substrate. Inactivation is due to the formation of a stable 1:1 enzyme inhibitor complex as a result of the active site serine being sulfonylated by the beta-sultam. Ring opening of the beta-sultam occurs by S-N fission in contrast to the C-N fission observed in the acylation of elastase by N-acylsulfonamides. Structure-activity effects are compared between sulfonylation of the enzyme and alkaline hydrolysis. Variation in 4-alkyl and N-substituted beta-sultams causes differences in the rates of inactivation by 4 orders of magnitude.

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