- Discovery of methylsulfonyl indazoles as potent and orally active respiratory syncytial Virus(RSV) fusion inhibitors
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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.
- Feng, Song,Li, Chao,Chen, Dongdong,Zheng, Xiufang,Yun, Hongying,Gao, Lu,Shen, Hong C.
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- Novel indazoles for the treatment and prophylaxis of respiratory syncytial virus infection
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The invention provides novel compounds having the general formula: wherein R1, R2, R3, R4, R5, R7, A1, A2 and A3 are as described herein, compositions including the compounds and methods of using the compounds.
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Paragraph 0378
(2015/06/17)
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- ORGANIC COMPOUNDS
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The invention relates to compounds of the general formula (I), wherein R1, R2, Q, X, m and n have the meanings given in the claims, and optionally the enantiomers thereof. The active ingredients have advantageous pesticidal properties. They are especially suitable for controlling parasites on warm-blooded animals and plants.
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Page/Page column 24
(2008/12/06)
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