Free-Wilson and correlation analysis were combined to study a series of 34 pepstatin analogues in which mainly position 2 was varied. A statistically highly significant correlation was found between the inhibitory activity of the analogues on an enriched plasma renin preparation and structural parameters of the amino acid side chain in position 2. The crucial parameters were found to be the NMR chemical shift of the alpha-carbon, the localized electrical (inductive) effect, and the van der Waals radius related steric parameter, which demonstrated the dominating influence of electronic inductive effects compared to steric bulk. The model gives insight into the structural requirements for effective inhibition and suggests the histidine-2 derivative, a positive outlier in this series, as a lead compound for further structure-activity studies.

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