Abstract

1. EST64401 and EST64514 are two selective sigma-1 receptor ligands that showed a good profile in a lead optimization process for oral pain treatment. Their potential for pharmacokinetic-based drug-drug interactions was assessed to anticipate clinical interactions.

2. Both compounds showed a low potential for CYP inhibition with percentages of inhibition <50% at 1 µM in recombinant human CYPs (CYP1A2, 2C9, 2C19, 2D6 and 3A4) and IC₅₀ ≥75 µM for CYP3A4 and 2D6 in human liver microsomes.

3. No CYP induction was observed for CYP1A2, 2B6 and 3A4 at concentrations ≤25 µM (EST64401) or ≤50 µM (EST64514) in human hepatocytes using as endpoints CYP activities and mRNA levels.

4. More than one enzyme participated in compound metabolism. The main enzymes involved were CYP3A4 for EST64401 and CYP2D6 besides CYP3A4 for EST64514.

5. Neither EST64401 nor EST64514 seemed to be substrates of P-gp or BCRP in Caco-2 cells (efflux ratio ≤2). Transporter inhibition was observed at concentrations ≥20 µM; EST64401 only inhibiting P-gp at higher concentrations (≥125 µM).

6. Preliminary in vitro interaction studies suggest a similar profile for EST64401 and EST64514. Therefore, other properties will have to be considered for compound differentiation and selection for further development.

 抽象的

1. 
   EST64401 和 EST64514 是两种选择性 sigma-1 受体配体，在口腔疼痛治疗的先导化合物优化过程中表现出良好的特性。评估它们基于药代动力学的药物相互作用的潜力，以预测临床相互作用。

2. 
   两种化合物均表现出较低的 CYP 抑制潜力，对人肝微粒体中的 CYP3A4 和 2D6 的抑制百分比 <50 id=19>50 ≥75 µM。

3. 
   使用 CYP 活性和 mRNA 水平作为终点，在人肝细胞中，浓度≤25 µM (EST64401) 或≤50 µM (EST64514) 时，未观察到 CYP1A2、2B6 和 3A4 的 CYP 诱导。

4. 
   不止一种酶参与化合物代谢。 EST64401 涉及的主要酶是 CYP3A4，EST64514 涉及的主要酶是 CYP3A4 和 CYP2D6。

5. 
   EST64401 和 EST64514 似乎都不是 Caco-2 细胞中 P-gp 或 BCRP 的底物（流出比 ≤2）。在浓度≥20 µM 时观察到转运蛋白抑制； EST64401 仅在较高浓度 (≥125 µM) 时抑制 P-gp。

6. 
   初步体外相互作用研究表明 EST64401 和 EST64514 具有相似的特征。因此，必须考虑其他特性来进行化合物的分化和选择，以进行进一步的开发。