Evaluation of Larger Side-Group Functionalities and the Side/End-Group Interplay in Ritonavir-Like Inhibitors of CYP3A4.

Eric R Samuels, Irina F Sevrioukova
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Abstract

A new series of 13 ritonavir-like inhibitors of human drug-metabolizing CYP3A4 was rationally designed to study the R2 side-group and R3 end-group interplay when the R1 side-group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R1/R2-phenyl inhibitors upon elongation and/or fluorination of R3-Boc (tert-butyloxycarbonyl) or its replacement with benzenesulfonyl. When R3 is pyridine, the impact of R2-phenyl-to-indole/naphthalene substitution was multidirectional and highly dependent on side-group stereo configuration. Overall, the R2-naphthalene/R3-pyridine containing 2f (R/S) was the series lead compound and one of the strongest binders/inhibitors designed thus far (Ks = 0.009 μM; IC50 = 0.10 μM). Introduction of a larger biphenyl or fluorene as R2 did not lead to any improvements. Contrarily, fluorene-containing 13 was the series weakest binder and inhibitor (Ks = 0.734 μM; IC50 = 1.32 μM), implying that the fluorene moiety is too large to allow unrestricted access to the active site. The R2-biphenyl, however, can switch positions with R3-Boc to enable heme ligation. Thus, for small and chemically simple end-groups such as Boc and pyridine, the R2/R3 interplay could lead to conformational rearrangement that would be difficult to foresee without structural information.

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利托那韦类CYP3A4抑制剂更大侧组功能和侧/端组相互作用的评估
合理设计了13个新的利托那韦类人药物代谢CYP3A4抑制剂系列,以研究R1侧组以苯基为代表时R2侧组与R3端组的相互作用。光谱、功能和结构表征表明,R1/ r2 -苯基抑制剂在延伸和/或氟化R3-Boc(叔丁氧羰基)或被苯磺酰取代后,其结合亲和力和抑制效力没有改善。当R3为吡啶时,r2 -苯基对吲哚/萘取代的影响是多向的,并且高度依赖于侧基立体构型。总的来说,含2f (R/S)的r2 -萘/ r3 -吡啶是系列先导化合物,也是迄今为止设计的最强的结合剂/抑制剂之一(Ks = 0.009 μM;ic50 = 0.10 μm)。引入较大的联苯或芴作为R2并没有带来任何改善。相反,含芴13是系列最弱的粘结剂和抑制剂(Ks = 0.734 μM;IC50 = 1.32 μM),这意味着芴基团太大,无法无限制地进入活性位点。然而,r2 -联苯可以与R3-Boc交换位置以实现血红素连接。因此,对于小的和化学上简单的端基,如Boc和吡啶,R2/R3的相互作用可能导致构象重排,如果没有结构信息,这种重排是很难预测的。
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