Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties
- 14 May 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (9), 4837-4848
- https://doi.org/10.1021/acs.jmedchem.0c00117
Abstract
The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9a(res) strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.Funding Information
- China Postdoctoral Science Foundation (2019T120596)
- Taishan Scholar Project of Shandong Province
- Shandong University (2016WLJH32)
- National Natural Science Foundation of China (81420108027, 8190345, 81973181)
- Natural Science Foundation of Shandong Province (ZR2019BH011)
- Shandong Provincial Key Research and Development Project (2017CXGC1401, 2019JZZY021011)
This publication has 28 references indexed in Scilit:
- Thermodynamics of HIV-1 Reverse Transcriptase in Action Elucidates the Mechanism of Action of Non-Nucleoside InhibitorsJournal of the American Chemical Society, 2013
- Novel Pyridinone Derivatives As Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with High Potency against NNRTI-Resistant HIV-1 StrainsJournal of Medicinal Chemistry, 2013
- Development of Antiretroviral Drug ResistanceThe New England Journal of Medicine, 2011
- Mutations in Human Immunodeficiency Virus Type 1 Integrase Confer Resistance to the Naphthyridine L-870,810 and Cross-Resistance to the Clinical Trial Drug GS-9137Antimicrobial Agents and Chemotherapy, 2008
- Tetrazolium-based colorimetric assay for the detection of HIV replication inhibitors: revisited 20 years laterNature Protocols, 2008
- Overcoming Undesirable hERG Potency of Chemokine Receptor Antagonists Using Baseline Lipophilicity RelationshipsJournal of Medicinal Chemistry, 2008
- Drug–drug interactions in the metabolism of imidafenacin: Role of the human cytochrome P450 enzymes and UDP-glucuronic acid transferases, and potential of imidafenacin to inhibit human cytochrome P450 enzymesXenobiotica, 2007
- Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic DrugsThe Journal of pharmacology and experimental therapeutics, 2005
- Optimization of a genotypic assay applicable to all human immunodeficiency virus type 1 protease and reverse transcriptase subtypesJournal of Virological Methods, 2005
- Poly A-linked colorimetric microtiter plate assay for HIV reverse transcriptaseJournal of Virological Methods, 1993