Development of a generalized, quantitative physicochemical model of CYP3A4inhibition for use in early drug discovery

Purpose. To examine the structure-activity relationships for the inhibition of the activity of recombinant human CYP3A4 and to establish a generalized , quantitative physicochemical model for use in early drug discovery., Methods, Inhibition of the activity of recombinant human CYP3A4 (erythromyc in N-demethylase) by 30 diverse chemicals was studied using enhanced throug hput methodology. Results. There was a general, strong correlation between the IC50 value det ermined against erythromycin N-demethylase activity and Lipophilicity (LogD (7.4)) (r(2) = 0.68, p <0.0001). This relationship was strengthened further by subdividing the structures studied into two distinct subpopulations of chemistry within the dataset. These could be identified by the absence (r(2 ) = 0.80, p <0.0001) or presence (r(2) = 0.69, p <0.0001) of a sterically u ninhindered N-containing heterocycle, more specifically a pyridine, imidazo le, or triazole function. The presence of these structural motifs increased the potency of CYP3A4 inhibition by approximately 10-fold for a given lipo philicity (LogD(7.4).value). More detailed analyses of AstraZeneca compound s demonstrated that the inhibitory potency of the pyridine structure can be attenuated through direct steric effects or electronic substitution result ing in a modulation of the pKa of the pyridine nitrogen. thereby influencin g its ability to interact with the CYP heme. Conclusions. A generalized, quantitative model is proposed for the inhibiti on of the major drug metabolizing enzyme, CYP3A4. This model indicates the importance of lipophilicity and rationalizes increased potency arising thro ugh additional interactions with the heme iron. These general relationships were shown to be applicable to a selection of compounds of interest to sev eral early research projects.