Discovery of methylsulfonyl indazoles as potent and orally active respiratory syncytial Virus(RSV) fusion inhibitors
- Eur J Med Chem. 2017 Sep 29:138:1147-1157. doi: 10.1016/j.ejmech.2017.07.032.
- 1. Medicinal Chemistry, Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China. Electronic address: [email protected].
- 2. Medicinal Chemistry, Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
- 3. Discovery Virology, Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
Recently we described a novel class of imidazopyridine compounds that showed exceptional anti-RSV potency in Cell Culture. However, unfavorable pharmacokinetic (PK) properties and glutathione (GSH) adduct liabilities impeded their further development. In a bid to address the PK and early safety concerns, a small compound library consisting of dozens of scaffold-hopping analogues was designed and synthesized for RSV CPE assay screening, which led to the identification of a new chemical starting point: methylsulfonyl indole compound 8. In this paper, we report the discovery and optimization of a series of methylsulfonyl indazoles as potent RSV fusion inhibitors. In particular, compound 47 was orally efficacious in a RSV mouse model, with 1.6 log unit viral load reduction at 25 mg/kg BID upon oral dosing. The results may have broad implications for the design of new RSV fusion inhibitors, and demonstrate the potential for developing novel therapies for RSV Infection.