N-Aryl Indoles as a Novel Class of Potent NaV1.7 Inhibitors

Abstract

A novel class of potent Na_V1.7 inhibitors has been discovered. The replacement of diaryl ether in compound I was investigated to enhance mouse Na_V1.7 inhibitory activity, which resulted in the discovery of N-aryl indoles. The introduction of the 3-methyl group is crucial for high Na_V1.7 in vitro potency. The adjustment of lipophilicity led to the discovery of 2e. Compound 2e (DS43260857) demonstrated high in vitro potencies against both human and mouse Na_V1.7 with high selectivity over Na_V1.1, Na_V1.5, and hERG. In vivo evaluations revealed 2e demonstrating potent efficacy in PSL mice with excellent pharmacokinetics.

Figure 1

Na_V1.7 inhibitor I reported by the Pfizer group with IC₅₀ values and molecular design of novel indole derivatives A and B. Data were obtained with a high-throughput electrophysiology system (IonWorks Quattro) in-house. Values are from a single experiment run in quadruplicate.

Figure 2

Time course of PWL (s) induced by compounds 1p, 2e, and 2g. The effect of compounds on thermal hyperalgesia in PSL mice. The compound was administered p.o. in 0.5% MC in three experiments (n = 4). Normal and vehicle groups are indicated based on three pooled experiments (n = 12), whereas normal and vehicle groups at 240 min are indicated based on two pooled experiments (n = 8). The analgesic efficacy of 1p at 240 min was not measured. Each value is the mean ± SEM. Statistical significance compared with vehicle treatment is denoted by *(p < 0.05), **(p < 0.01), as determined by the Aspin–Welch’s or Student’s t-test.

Figure 3

Time course of PK study after oral administration 1p (n = 3), 2e (n = 3), and 2g (n = 2). The compounds in 0.5% MC were administered to ddY mice at 1 mg/kg (p.o.). Each value is the mean ± SD.