Carbenoid-involved Reactions Integrated with Scaffold-based Screening Generates a Nav1.7 Inhibitor

Overview

Journal Commun Chem

Publisher Springer Nature

Specialty Chemistry

Date 2024 Jun 12

PMID 38866907

Authors

Jirong Shu

Yuwei Wang

Weijie Guo

Tao Liu

Song Cai

Taoda Shi

Wenhao Hu

Affiliations

Soon will be listed here.

Abstract

The discovery of selective Nav1.7 inhibitors is a promising approach for developing anti-nociceptive drugs. In this study, we present a novel oxindole-based readily accessible library (OREAL), which is characterized by readily accessibility, unique chemical space, ideal drug-like properties, and structural diversity. We used a scaffold-based approach to screen the OREAL and discovered compound C4 as a potent Nav1.7 inhibitor. The bioactivity characterization of C4 reveals that it is a selective Nav1.7 inhibitor and effectively reverses Paclitaxel-induced neuropathic pain (PINP) in rodent models. Preliminary toxicology study shows C4 is negative to hERG. The consistent results of molecular docking and molecular simulations further support the reasonability of the in-silico screening and show the insight of the binding mode of C4. Our discovery of C4 paves the way for pushing the Nav1.7-based anti-nociceptive drugs forward to the clinic.

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