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- W4378782074 abstract "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-à-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." @default.
- W4378782074 created "2023-06-01" @default.
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- W4378782074 date "2023-05-31" @default.
- W4378782074 modified "2023-10-14" @default.
- W4378782074 title "Escaping from Flatland: Multiparameter Optimization Leads to the Discovery of Novel Tetrahydropyrido[4,3-<i>d</i>]pyrimidine Derivatives as Human Immunodeficiency Virus-1 Non-nucleoside Reverse Transcriptase Inhibitors with Superior Antiviral Activities against Non-nucleoside Reverse Transcriptase Inhibitor-Resistant Variants and Favorable Drug-like Profiles" @default.
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- W4378782074 doi "https://doi.org/10.1021/acs.jmedchem.3c00275" @default.
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