An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4.

Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R ₁ side-group as phenyl or naphthalene and R ₂ as indole or naphthalene in different stereo configuration showed that (i) analogues with the R ₂ -naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R ₂ -phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R ₁ /R ₂ configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC ₅₀ of 0.055-0.085 μM vs. 0.130 μM, respectively).
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Published by Elsevier Ltd.)