Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 7. 8-Arylethyldipyridodiazepinones as Potent Broad-Spectrum Inhibitors of Wild-Type and Mutant Enzymes

Klunder, Janice M.; Hoermann, MaryAnn; Cywin, Charles L.; David, Eva; Brickwood, Janice R.; Schwartz, Racheline; Barringer, Kevin J.; Pauletti, Daniel; Shih, Cheng-Kon; Erickson, David A.; Sorge, Christopher L.; Joseph, David; Hattox, Susan E.; Adams, Julian; Grob, Peter M.

doi:10.1021/jm9707028

Cited by 35 publications

(33 citation statements)

References 33 publications

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“…Significant examples are diaryltriazine (Janssen [NJ, USA]) [71], dipyridodiazepinone BIRL 355 BS (Boehringer Ingelheim [CT, USA]) [72,73] and the pyrrolidin-1-ylsulfone (Merck [PA, USA]) [74] HIV-1 NNRTIs. The binding poses of IAS derivatives carrying an (hetero)cyclic moiety at the 2-carboxamide bridging group were predicted to resemble those of 53, 55 and 71 [50,51] establishing novel binding interactions in the solvent accessible cleft of the NNBS formed by residues R172, I180, V179 and E138:B, and T139:B.…”

Section: Peptide Derivativesmentioning

confidence: 99%

Arylsulfone-Based HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

et al. 2013

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HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent one of the most significant classes of drugs for the treatment of AIDS/HIV infection. Over the past two decades several potent arylsulfone-based HIV-1 NNRTIs and related analogs have been developed. This review provides an essential overview of the structure-activity relationships of the arylsulfone-based HIV-1 NNRTIs. Furthermore, structural information useful for the design and development of new sulfur containing NNRTIs with enhanced antiretroviral activity against HIV-1 wild type and clinically relevant drug resistant HIV-1 mutant strains will be discussed.

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Section: Peptide Derivativesmentioning

confidence: 99%

Arylsulfone-Based HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

et al. 2013

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“…For this reason, Boehringer Ingelheim has carried out modifications in the NVP structure to improve its resistance profile toward mutants. One of the possible modifications was the extension at position 8 on the tricyclic skeleton ( 69 ), to favor additional interactions with the backbone of P236 and K101, enhance potency, and reduce mutation impact occurring at any residue . The metabolic instability and poor bioavailability of this series of inhibitors has led to the generation of a new series of compounds containing an ethoxy linker ( 70 ‐ 71 ; Figure ) .…”

Section: Drug Design Strategiesmentioning

confidence: 99%

Challenges and approaches in the discovery of human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors

Battini

Bollini

2018

Medicinal Research Reviews

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The type I human immunodeficiency virus (HIV‐1) pandemic affecting over 37 million people worldwide continues, with 1.8 million people newly infected each year. Highly active antiretroviral therapy is efficient at reducing viral load and nearly one‐half of the infected population is on treatment. One of the most successful approaches for the treatment of HIV infections is the use of inhibitors for human immunodeficiency virus type‐1 reverse transcriptase (HIV‐1 RT). At present, there are six nonnucleoside reverse transcriptase inhibitors (NNRTIs) approved for clinical use: nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETV), rilpivirine (RPV), and elsulfavirine. In this review, we will cover the development of different classes of NNRTIs over the last two decades. We will give an overview of traditional medicinal chemistry strategies for structural modification as bioisosterism principles, scaffold hopping, substitute decoration, and molecular hybridization. Furthermore, computer‐aid design as virtual screening, de novo design and free‐energy perturbation will be described in details.

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“…10 Resistance to nevirapine was traced to a single mutation in the reverse transcriptase. 5,11 To overcome this resistance, it was necessary to design and develop protease inhibitors that pick up potency from interaction with amino-acid residues located on the side chain surrounding the binding pocket of nevirapine. Thus, by introducing appropriate substituents on the tricyclic moiety of nevirapine multiple interactions with this enzyme were achieved.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of [¹⁴C]‐ and [¹³C₆]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

Latli

Hrapchak

Busacca

et al. 2008

Labelled Comp Radiopharmac

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5,11-Dihydro-11-ethyl-5-methyl-8-{2-{(1-oxido-4-quinolinyl)oxy}ethyl}-6H-dipyrido[3,2-b:2 0 ,3 0 -e][1,4]diazepin-6-one, (1), labeled with carbon-14 in the quinoline-benzene ring, in one of the pyridine rings of the dipyridodiazepinone tricyclic moiety, and in the side chain, was prepared in three different syntheses with specific activities ranging from 44 to 47 mCi/mmol (1.63-1.75 GBq/mmol). In the first synthesis, 5,11 ,4]diazepin-6-one (2) was coupled to 4-hydroxyquinoline, [benzene-14 C(U)]-, using Mitsunobu's reaction conditions, followed by the oxidation of the quinoline nitrogen with 3-chloroperoxybenzoic acid to give ([ 14 C]-(1a)) in 43% radiochemical yield. Second, 3-amino-2-chloropyridine, [2,6-14 C]-, was used to prepare 8-bromo-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2 0 ,3 0 -e][1,4]diazepin-6-one (8), and then Stille coupled to allyl(tributyl)tin followed by ozonolysis of the terminal double bond and in situ reduction of the resulting aldehyde to alcohol (10). Mitsunobu etherification and oxidation as seen before gave ([ 14 C]-(1b)) in eight steps and in 11% radiochemical yield. Finally, carbon-14 potassium cyanide was used to prepare isopropyl cyanoacetate (12), which was used to transform bromide (8) to labeled aryl acetic acid (13) under palladium catalysis. Trihydroborane reduction of the acid gave alcohol (14) labeled in the side chain, which was used as described above to prepare ([ 14 C]-(1c)) in 4.3% radiochemical yield. The radiochemical purities of these compounds were determined by radio-HPLC and radio-TLC to be more than 98%. To prepare [ 13 C 6 ]-(1), [ 13 C 6 ]-4-hydroxyquinoline was prepared from [ 13 C 6 ]-aniline and then coupled to (2) and oxidized as seen before.

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Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 7. 8-Arylethyldipyridodiazepinones as Potent Broad-Spectrum Inhibitors of Wild-Type and Mutant Enzymes

Cited by 35 publications

References 33 publications

Arylsulfone-Based HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Arylsulfone-Based HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Challenges and approaches in the discovery of human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors

Synthesis of [¹⁴C]‐ and [¹³C₆]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

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Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 7. 8-Arylethyldipyridodiazepinones as Potent Broad-Spectrum Inhibitors of Wild-Type and Mutant Enzymes

Cited by 35 publications

References 33 publications

Arylsulfone-Based HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Arylsulfone-Based HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Challenges and approaches in the discovery of human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors

Synthesis of [14C]‐ and [13C6]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

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Synthesis of [¹⁴C]‐ and [¹³C₆]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor