Discovery of (aza)indole derivatives as novel respiratory syncytial virus fusion inhibitors

Abstract

A new class of (aza)indole derivatives have been identified as potent RSV fusion inhibitors.

Recent Progress toward the Discovery of Small Molecules as Novel Anti-Respiratory Syncytial Virus Agents

“…49 However, compound 2 still had unsatisfactory PK properties, leading to a second round of optimization in 2019 resulting in the development of a series of 6-aza-spirooxindole derivatives. 50 Functionalization of the indole benzene portion with various halogens or small groups and of the indole N-1 position with different sulfur-containing chains led to the identification of compound 3 (Figure 4), which exhibited high potency (EC 50 = 2 nM) and promising PK properties. The in vivo PK profile of 3 demonstrated an oral bioavailability in male ICR mice of 24.5% (16.9% for compound 2) and a T 1 / 2 of 3.04 h (1.73 h for 2).…”

“…In a cellular context, the targeting of the F protein was demonstrated by inhibiting the syncytia formation process using 10 nM of compound 3. 50 To the best of our knowledge, the compound has not yet been subjected to clinical trials.…”

“…Compound 2 demonstrated a human microsome clearance of 2.5 mL/min/kg and a CYP3A4 IC 50 > 50 μM, indicating improved PK properties compared to compound 1 (16.3 mL/min/kg and IC 50 27.5 μM) . However, compound 2 still had unsatisfactory PK properties, leading to a second round of optimization in 2019 resulting in the development of a series of 6-aza-spirooxindole derivatives . Functionalization of the indole benzene portion with various halogens or small groups and of the indole N-1 position with different sulfur-containing chains led to the identification of compound 3 (Figure ), which exhibited high potency (EC 50 = 2 nM) and promising PK properties.…”

“…The in vivo PK profile of 3 demonstrated an oral bioavailability in male ICR mice of 24.5% (16.9% for compound 2 ) and a T 1 / 2 of 3.04 h (1.73 h for 2 ). In a cellular context, the targeting of the F protein was demonstrated by inhibiting the syncytia formation process using 10 nM of compound 3 . To the best of our knowledge, the compound has not yet been subjected to clinical trials.…”