期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 66, 期 13, 页码 8643-8665出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c00275
关键词
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This study discovered a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives with broad-spectrum antiviral activity and improved resistance profiles against NNRTI-resistant variants. The most potent inhibitor 10c exhibited desirable physicochemical properties and in vitro metabolic stability. It also showed lower cytochrome P450 inhibition and human ether-a-go-go-related gene blockade liability compared to currently available medications.
In the current landscape of antiretroviral options, there remains an urgent need for novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved resistance profiles and safety properties. Herein, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives were discovered utilizing the escape from flatland strategy. The most potent inhibitor 10c was endowed with broad-spectrum antiviral activity and improved resistance profiles against NNRTI-resistant variants compared to efavirenz and etravirine. Molecular simulations were investigated to furnish insights into the biological results. Drug-likeness assessment showed that 10c exhibited desirable physicochemical properties and in vitro metabolic stability. Notably, lower cytochrome P450 inhibition and human ether-a-go-go-related gene blockade liability were observed for 10c than those for etravirine and rilpivirine. Besides, 10c was characterized by excellent in vivo safety properties without acute/subacute toxicity and organ pathological damage. Overall, our multiparameter optimization campaign led to the identification of 10c with excellent antiviral activities and favorable drug-like profiles that could serve as an ideal drug candidate for further development.
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