Discovery of a Quinazoline-Based Nav1.7 Inhibitor with MicroED-Confirmed Absolute Configuration and Oral Efficacy in Rodent Models of Neuropathic Pain

Abstract

Selective Nav1.7 inhibition is a genetically validated, non-opioid strategy for chronic neuropathic pain. Herein, we report the structure-guided discovery of a quinazoline-based Nav1.7 inhibitor series. From a focused-library hit A1 (IC50 = 15.2 μM), systematic SAR across 19 analogs yielded the chiral lead (R)-(+)-A11 (IC50 = 0.98 μM; 53.9-fold selectivity over Nav1.5), with absolute configuration confirmed by MicroED (Flack x = 0.03(12)). (R)-(+)-A11 displayed favorable oral pharmacokinetics (F = 28.2%, free Cmax = 1.06 μM) and dose-dependent analgesia in mouse formalin (ED50 = 18.5 mg/kg) and rat CCI (83% MPE; ED50 = 17.1 mg/kg) models. Off-target profiling of A11 (racemate) against 44 targets showed <10% inhibition at 10 μM, and DRG CGRP target engagement by (R)-(+)-A11 (IC50 = 0.42 μM), with Nav1.7-KO neuron controls supporting Nav1.7 as the primary mechanism. These results establish (R)-(+)-A11 as a promising quinazoline lead for non-opioid neuropathic pain therapeutics.