2-Pyridyl P1′-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors (A-792611 and A-790742) with Potential for Convenient Dosing and Reduced Side Effects

DeGoey, David A.; Grampovnik, David J.; Flentge, Charles A.; Flosi, William J.; Chen, Hui-Ju; Yeung, Clinton M.; Randolph, John T.; Klein, Larry L.; Dekhtyar, Tatyana; Colletti, Lynn; Marsh, Kennan C.; Stoll, V.S.; Mamo, M.; Morfitt, David C.; Nguyen, Bach; Schmidt, James M.; Swanson, Sue; Mo, Hongmei; Kati, Warren M.; Molla, Akhteruzzaman; Kempf, Dale J.

doi:10.1021/jm900044w

Cited by 26 publications

(25 citation statements)

References 31 publications

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“…Subsequently, docking of rifampicin was started after superimposing the hPXR-rifampicin complex 1SKX (Chrencik et al, 2005) onto 1M13. The PXR antagonist A-792611 was built from the similar HIV-protease inhibitor in Protein Data Bank ID 3GGV (Degoey et al, 2009), guided by the structure drawing from Healan-Greenberg et al (2008). The other compounds (ketoconazole, paclitaxel, erlotinib, and milk thistle's components) were obtained as Sybyl Mol2 files from ChemIDplus Advanced (http://chem.sis.nlm.nih.gov/chemidplus/; National Institutes of Health, Bethesda, MD).…”

Section: Cyp3a4 Reporter Gene Assaymentioning

confidence: 99%

Milk Thistle’s Active Components Silybin and Isosilybin: Novel Inhibitors of PXR-Mediated CYP3A4 Induction

et al. 2013

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Because cancer is often treated with combination therapy, unexpected pharmacological effects can occur because of drug-drug interactions. Several drugs are able to cause upregulation or downregulation of drug transporters or cytochrome P450 enzymes, particularly CYP3A4. Induction of CYP3A4 may result in decreased plasma levels and therapeutic efficacy of anticancer drugs. Since the pregnane X receptor (PXR) is one of the major transcriptional regulators of CYP3A4, PXR antagonists can possibly prevent CYP3A4 induction. Currently, a limited number of PXR antagonists are available. Some of these antagonists, such as sulphoraphane and coumestrol, belong to the so-called complementary and alternative medicines (CAM). Therefore, the aim was to determine the potential of selected CAM (b-carotene, Echinacea purpurea, garlic, Ginkgo biloba, ginseng, grape seed, green tea, milk thistle, saw palmetto, valerian, St. John's Wort, and vitamins B 6 , B 12 , and C) to inhibit PXR-mediated CYP3A4 induction at the transcriptional level, using a reporter gene assay and a real-time polymerase chain reaction assay in LS180 colon adenocarcinoma cells. Furthermore, computational molecular docking and a LanthaScreen time-resolved fluorescence resonance energy transfer (TR-FRET) PXR competitive binding assay were performed to explore whether the inhibiting CAM components interact with PXR. The results demonstrated that milk thistle is a strong inhibitor of PXR-mediated CYP3A4 induction. The components of milk thistle responsible for this effect were identified as silybin and isosilybin. Furthermore, computational molecular docking revealed a strong interaction between both silybin and isosilybin and PXR, which was confirmed in the TR-FRET PXR assay. In conclusion, silybin and isosilybin might be suitable candidates to design potent PXR antagonists to prevent drug-drug interactions via CYP3A4 in cancer patients.

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Section: Cyp3a4 Reporter Gene Assaymentioning

confidence: 99%

Milk Thistle’s Active Components Silybin and Isosilybin: Novel Inhibitors of PXR-Mediated CYP3A4 Induction

et al. 2013

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“…Hindered ortho-substituted aryl lithium reagents ( 9e ) as well as electron-deficient aryllithium reagents ( 9f ) reacted smoothly in Et 2 O with moderate heating (45 °C). We were particularly interested in the 2-pyridyl subunit given the prevalence of this structural unit in pharmaceuticals 16 and natural products. 17 We note that CCRs of 2-pyridyl moieties remain a challenging transformation.…”

mentioning

confidence: 99%

Design, Synthesis, and Validation of an Effective, Reusable Silicon-Based Transfer Agent for Room-Temperature Pd-Catalyzed Cross-Coupling Reactions of Aryl and Heteroaryl Chlorides with Readily Available Aryl Lithium Reagents

et al. 2016

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A reusable silicon-based transfer agent (1) has been designed, synthesized, and validated for effective room-temperature palladium-catalyzed cross-coupling reactions (CCRs) of aryl and heteroaryl chlorides with readily accessible aryl lithium reagents. The crystalline, bench-stable siloxane transfer agent (1) is easily prepared via a one-step protocol. Importantly, this “green” CCR protocol circumvents prefunctionalization, isolation of organometallic cross-coupling partners, and/or stoichiometric waste aside from LiCl. DFT calculations support a σ-bond metathesis mechanism during transmetalation and lead to insights on the importance of the CF3 groups.

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“…[53] DeGoey et al at Abbottdesigned new imidazolidinones with fewer side effects (hyperbilirubinemia). Hyperbilirubinemia is ac ommon side effect of HIV protease inhibitors.…”

Section: Targets Of Anti-hivdrugsmentioning

confidence: 99%

Imidazolidinones and Imidazolidine‐2,4‐diones as Antiviral Agents

Swain

Mohanty

2019

ChemMedChem

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Imidazolidinones and imidazolidine‐2,4‐diones are important classes of heterocyclic compounds that possess potent activities against several viruses such as dengue virus, enterovirus, hepatitis C virus (HCV), and human immunodeficiency virus (HIV). The first imidazolidinone derivative as an anti‐HIV agent was reported in 1996. Imidazolidinones inhibit HIV aspartic protease activity, and also act as CCR5 co‐receptor antagonists. Significant effort has been devoted to the design of various imidazolidinone analogues that are active against drug‐resistant HIV strains, with fewer side effects. Different scaffolds have been designed through both rational drug design strategies and computer‐aided drug design. Imidazolidinones have been found to be potent against HIV, and preclinical studies are currently in progress. There are some reports of imidazolidinones as having both anti‐HCV and anti‐dengue virus activity, and more research has yet to be done along these lines. These compounds inhibit NS3 serine protease of HCV, and NS2B‐NS3 protease of dengue virus. Pyridyl‐imidazolidinones possess very specific and potent activity against human enterovirus 71 (EV71) by targeting the EV71 capsid protein VP1, and inhibiting viral adsorption and/or viral RNA uncoating.

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2-Pyridyl P1′-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors (A-792611 and A-790742) with Potential for Convenient Dosing and Reduced Side Effects

Cited by 26 publications

References 31 publications

Milk Thistle’s Active Components Silybin and Isosilybin: Novel Inhibitors of PXR-Mediated CYP3A4 Induction

Milk Thistle’s Active Components Silybin and Isosilybin: Novel Inhibitors of PXR-Mediated CYP3A4 Induction

Design, Synthesis, and Validation of an Effective, Reusable Silicon-Based Transfer Agent for Room-Temperature Pd-Catalyzed Cross-Coupling Reactions of Aryl and Heteroaryl Chlorides with Readily Available Aryl Lithium Reagents

Imidazolidinones and Imidazolidine‐2,4‐diones as Antiviral Agents

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