- 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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p. 1147 - 1157
(2017/08/02)
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- Directed ortho -metalation-cross-coupling strategies. One-pot Suzuki reaction to biaryl and heterobiaryl sulfonamides
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A general synthesis of stable ortho-boropinacolato aryl and heteroaryl sulfonamides by directed ortho-metalation (DoM) and either MeOBPin or i-PrOBpin electrophile quench, 3 → 4, is described. A one-pot metalation-Suzuki cross-coupling procedure for the synthesis of biaryls and heterobiaryls, 3 → 5, and a complementary DoM-Ir-catalyzed boronation sequence (Scheme 6) are delineated.
- Schneider, Cedric,Broda, Ellen,Snieckus, Victor
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p. 3588 - 3591
(2011/10/03)
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- Design and synthesis of human immunodeficiency virus entry inhibitors: Sulfonamide as an isostere for the α-ketoamide group
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The crystal structures of many tertiary α-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the α-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a s
- Lu, Rong-Jian,Tucker, John A.,Zinevitch, Tatiana,Kirichenko, Olga,Konoplev, Vitalii,Kuznetsova, Svetlana,Sviridov, Sergey,Pickens, Jason,Tandel, Sagun,Brahmachary, Enugurthi,Yang, Yang,Wang, Jian,Freel, Stephanie,Fisher, Shelly,Sullivan, Alana,Zhou, Jiying,Stanfield-Oakley, Sherry,Greenberg, Michael,Bolognesi, Dani,Bray, Brian,Koszalka, Barney,Jeffs, Peter,Khasanov, Alisher,Ma, You-An,Jeffries, Cynthia,Liu, Changhui,Proskurina, Tatiana,Zhu, Tong,Chucholowski, Alexander,Li, Rongshi,Sexton, Connie
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p. 6535 - 6544
(2008/09/16)
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