期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 20, 页码 8608-8621出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm501203v
关键词
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资金
- NIH [S10RR024664]
- NSF [0320648]
- [NIH U54HG005031]
- [NIH U54HG005034-01]
- [R03 MH087448-01A1]
- [NIH U54 HG00503]
Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause significant disease in humans. Given the absence of therapeutic options available and the significance of VEEV as a weaponized agent, an optimization effort was initiated around a quinazolinone screening hit 1 with promising cellular antiviral activity (EC50 = 0.8 mu M), limited cytotoxic liability (CC50 > 50 mu M), and modest in vitro efficacy in reducing viral progeny (63-fold at 5 mu M). Scaffold optimization revealed a novel rearrangement affording amidines, specifically compound 45, which was found to potently inhibit several VEEV strains in the low nanomolar range without cytotoxicity (EC50 = 0.02-0.04 mu M, CC50 > 50 mu M) while limiting in vitro viral replication (EC90 = 0.17 mu M). Brain exposure was observed in mice with 45. Significant protection was observed in VEEV-infected mice at 5 mg kg(-1) day(-1) and viral replication appeared to be inhibited through interference of viral nonstructural proteins.
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