Structure-Based Design of HIV Protease Inhibitors:  Sulfonamide-Containing 5,6-Dihydro-4-hydroxy-2-pyrones as Non-Peptidic Inhibitors

Thaisrivongs, Suvit; Skulnick, Harvey I.; Turner, Steve R.; Strohbach, Joseph W.; Tommasi, Rubén; Johnson, Paul D.; Aristoff, Paul A.; Judge, Thomas M.; Gammill, Ronald B.; Morris, Jeanette K.; Romines, Karen R.; Chrusciel, R. A.; Hinshaw, Roger R.; Chong, K. T.; Tarpley, W. G.; Poppe, Susan M.; Slade, Dea; Lynn, Janet C.; Horng, Miao-Miao; Tomich, Paul K.; Seest, Eric P.; Dolak, Lester A.; Howe, W. Jeffrey; Howard, G.M; Watenpaugh, Keith David

doi:10.1021/jm960541s

Cited by 101 publications

(52 citation statements)

References 36 publications

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“…The absolute stereochemistry of four stereoisomers of PNU-106893 (a 50/50 mixture of the pair of racemic diastereoisomers) were assigned based on the comparison of their physical and chemical properties to the known analogs. 3 [ 3 H]PNU-106893 with a tritium-specific activity of 44.01 mCi/mg (24.9 Ci/mmole) was also synthesized as a mixture of four stereoisomers by Pharmacia & Upjohn, Inc. with labeling on the aminophenyl ring (Fig. 1).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…1,2 Inhibitors of HIV protease have continued to receive much attention as potential therapeutic agents for the treatment of HIV infection. 3 PNU-106893 and its analogs are representative nonpeptide HIV-1 protease inhibitors under investigation as potential oral treatments for AIDS. 3 PNU-106893 is a mixture of two pairs of enantiomers and specific stereoisomers are PNU-109165 (3␣R, 6S), PNU-109166 (3␣R, 6R), PNU-109167 (3␣S, 6S), and PNU-109168 (3␣S, 6R).…”

mentioning

confidence: 99%

“…3 PNU-106893 and its analogs are representative nonpeptide HIV-1 protease inhibitors under investigation as potential oral treatments for AIDS. 3 PNU-106893 is a mixture of two pairs of enantiomers and specific stereoisomers are PNU-109165 (3␣R, 6S), PNU-109166 (3␣R, 6R), PNU-109167 (3␣S, 6S), and PNU-109168 (3␣S, 6R). Stereoselective protein association 4 and enantioselective pharmacokinetics 5 of this class of compounds have previously been reported.…”

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confidence: 99%

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Stereoselective hydroxylation of nonpeptidic HIV protease inhibitors by CYP2D6

Zhao

Koeplinger²,

Waldon³

1999

Chirality

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PNU‐106893, N‐{3‐[1‐(4‐hydroxy‐2‐oxo‐6‐phenyl‐6‐propyl‐5,6‐dihydro‐2H‐pyran‐3‐yl)‐2,2‐dimethylpropyl]phenyl}‐1‐methyl‐1H‐imidazole‐4‐sulfonamide, is a selective HIV aspartyl protease inhibitor under evaluation as a potential oral treatment of acquired immunodeficiency disease. PNU‐106893 is a mixture of four stereoisomers, designated PNU‐109165 (3αR, 6S), PNU‐109166 (3αR, 6R), PNU‐109167 (3αS, 6S), and PNU‐109168 (3αS, 6R). The major P450 isoforms involved in the metabolism of PNU‐106893 and its pure stereoisomers are identified as CYP2D6 and CYP3A4. The major oxidative biotransformation pathway of PNU‐106893 which occurs in microsomal incubations appears to be hydroxylation of the phenylethyl side chain attached to the C‐6 carbon of the dihydropyrone ring. This hydroxylation is mediated by CYP2D6 only and the process is stereoselective for the 6R absolute stereochemistry. The configuration at position 3 appears to play a minor role in the CYP2D6 mediated hydroxylation. These insights have impacted drug candidate selection for this class of compounds. Chirality 11:731–739, 1999. © 1999 Wiley‐Liss, Inc.

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Section: Chemicals and Reagentsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Stereoselective hydroxylation of nonpeptidic HIV protease inhibitors by CYP2D6

Zhao

Koeplinger²,

Waldon³

1999

Chirality

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“…The dihydro-2-pyrones isolated from microbial sources have shown a diverse range of biological activities. Some of their activities include anticancer, anti-HIV, antifungal, neurotoxic, cytotoxic, phytotoxic, and activities (Dickinson, 1993, Thaisrivongs et al, 1996Poppe et al, 1997;Turner et al, 1998). The mechanism of anticancer activity of 2-pyrones involves inhibition of DNA synthesis in the cells (Trachootham et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

5-Bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one targets prostate cancer cells by down-regulating inflammation-related genes

Wang

Zhang

et al. 2016

Bangladesh J Pharmacol

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The present study was performed to examine the effect of 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP) on the rate of cell proliferation and apoptosis induction in the PC3, human prostate carcinoma cell line. The cell viability was assayed by using sulphorhodamine B staining and apoptosis by annexin V and flow cytometry analyses. The results revealed that BHP treatment in PC3 cells caused a significant reduction in the rate of cell proliferation in dose-and time-dependent manner. Compared to the untreated cells, the formation of HUVEC tubes was markedly inhibited on treatment with BHP at a concentration of 30 µM. Further investigation revealed the expression of HMGB1, IL-6 and IL-8, pro-inflammatory cytokines was also inhibited on treatment with BHP. Therefore, BHP treatment plays an important role in inducing apoptosis in the prostrate cells and can be of therapeutic value for the prostate cancer treatment. Article InfoReceived:25 June 2015 Accepted:9 5-Bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one targets prostate cancer cells by down-regulating inflammation-related genes

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“…Broad screening efforts led to the discovery of 4-hydroxycoumarines with warfarin and phenprocoumon as first candidates of the second class of PIs. They also show direct binding to Ile50/50´ like cyclic ureas via oxygene atoms of the lactone structure [6]. Although PR inhibitory activities in the micromolar range was insufficient for therapy, excellent bioavailabilities and long half-lives encouraged for further developments (Fig.…”

Section: Introductionmentioning

confidence: 99%

Dimeric 4-Aryl-1,4-Dihydropyridines: Development of a Third Class of Nonpeptidic HIV-1 Protease Inhibitors

Hilgeroth¹

2002

MRMC

101

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Cross-resistance development against most peptidic HIV-1 protease inhibitors (PI) forces the development of nonpeptidic alternatives. The classes of nonpeptidic protease inhibitors was limited so far to cyclic ureas and 4-hydroxy-2-pyrones with problems of limited bioavailability by extensive metabolism and protein binding. Cage dimeric 4-aryl-1,4-dihydropyridines have been developed as third class of nonpeptidic PIs. In the following synthesis, molecular modeling and biological activities of a first series of the novel PIs are reviewed. Bioavailability of the dimers will not be limited by protein binding and metabolism as far as evaluated.

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Structure-Based Design of HIV Protease Inhibitors: Sulfonamide-Containing 5,6-Dihydro-4-hydroxy-2-pyrones as Non-Peptidic Inhibitors

Cited by 101 publications

References 36 publications

Stereoselective hydroxylation of nonpeptidic HIV protease inhibitors by CYP2D6

Stereoselective hydroxylation of nonpeptidic HIV protease inhibitors by CYP2D6

5-Bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one targets prostate cancer cells by down-regulating inflammation-related genes

Dimeric 4-Aryl-1,4-Dihydropyridines: Development of a Third Class of Nonpeptidic HIV-1 Protease Inhibitors

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