Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: The discovery of GW0385

Miller, John F.; Andrews, C. Webster; Brieger, Michael; Furfine, Eric S.; Hale, Michael R.; Hanlon, Mary H.; Hazen, Richard; Káldor, István; McLean, Ed W.; Reynolds, David J.; Sammond, Douglas M.; Spaltenstein, Andrew; Tung, Roger D.; Turner, Elizabeth M.; Xu, Renfeng; Sherrill, Ronald G.

doi:10.1016/j.bmcl.2006.01.035

Cited by 75 publications

(54 citation statements)

References 19 publications

(4 reference statements)

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“…Further studies were focused on optimization of the P1 position by exploring both aryl and heteroaryl ethers. 109 Inhibitor 38 displayed an impressive activity profile, with a wild-type IC 50 of 0.7 nM and IC 50 values of 4.8 nM and 1.1 nM against selected drug resistant variants (Table 8). When screened against a more extensive panel of ten multidrug-resistant HIV-1 mutants, 38 maintained potency with IC 50 values ranging from 0.22 nM to 8.2 nM, a 1–12-fold change.…”

Section: (5) Recent Progress Towards Hiv-1 Protease Inhibitorsmentioning

confidence: 99%

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

2016

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HIV-1 protease inhibitors continue to play an important role in the treatment of HIV/AIDS, transforming this deadly ailment into a more manageable chronic infection. Over the years, intensive research led to a variety of approved protease inhibitors for the treatment of HIV/AIDS. In this review, we outline current drug design and medicinal chemistry efforts toward the development of new generation protease inhibitors beyond the currently approved drugs.

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Section: (5) Recent Progress Towards Hiv-1 Protease Inhibitorsmentioning

confidence: 99%

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

2016

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“…In synthetic organic chemistry, the properties of boronic acids as mild Lewis acids have made them an attractive class of intermediates [25] that have been widely used in Suzuki cross-coupling reactions [3, 26], Diels-Alder reactions [27], asymmetric synthesis of amino acids [28], selective reduction of aldehydes [29], and carboxylic acid activation [30, 31]. Biochemical and medicinal applications of boronic acids include inhibitors of serine proteases and beta-lactamases [32–34], bioconjugates [35], transmembrane transporters [36–39], anti-HIV drugs [40, 41], substrates for protein immobilization [42], and agents in neutron capture therapy [43–45]. …”

Section: Introductionmentioning

confidence: 99%

Computational Investigation of the Oxidative Deboronation of Boroglycine, H₂N−CH₂−B(OH)₂, Using H₂O and H₂O₂

et al. 2009

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We report results from a computational investigation of the oxidative deboronation of BoroGlycine, H2N–CH2–B(OH)2, using H2O and H2O2 as the reactive oxygen species (ROS) to yield aminomethanol, H2N–CH2–OH; these results complement our study on the protodeboronation of BoroGlycine to produce methylamine, H2N–CH3 (Larkin et al. J. Phys. Chem. A, 111, 6489–6500, 2007). Second-order Møller-Plesset (MP2) perturbation theory with Dunning-Woon correlation-consistent (cc) basis sets were used for the calculations with comparisons made to results from Density Functional Theory (DFT) at the PBE1PBE/6-311++G(d,p)(cc-pVDZ) levels. The effects of a bulk aqueous environment were also incorporated into the calculations employing PCM and CPCM methodology. Using H2O as the ROS, the reaction H2O + H2N–CH2–B(OH)2 → H2N–CH2–OH + H–B(OH)2 was calculated to be endothermic, the value of normalΔH2980 was +12.0 kcal/mol at the MP2(FC)/cc-pVTZ computational level in vacuo and +13.7 kcal/mol in PCM aqueous media; the corresponding value for the activation barrier, ΔH‡, was +94.3 kcal/mol relative to the separated reactants in vacuo and +89.9 kcal/mol in PCM aqueous media. In contrast, the reaction H2O2 + H2N–CH2–B(OH)2 → H2N–CH2–OH + B(OH)3 was calculated to be highly exothermic with a normalΔH2980 value of −100.9 kcal/mol at the MP2(FC)/cc-pVTZ computational level in vacuo and −99.6 kcal/mol in CPCM aqueous media; the highest-energy transition state for the multi-step process associated with this reaction involved the rearrangement of H2N–CH2–B(OH)(OOH) to H2N–CH2–O–B(OH)2 with a ΔH‡ value of +23.2 kcal/mol in vacuo relative to the separated reactants. These computational results for BoroGlycine are in accord with the experimental observations for the deboronation of the FDA approved anti-cancer drug Bortezomib (Velcade™, PS-341) where it was found to be the principle deactivation pathway. (Labutti et al. Chem. Res. Toxicol., 19, 539–546, 2006).

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“…5 A number of other clinical protease inhibitors ( 2 , Brecanavir; 3 , GS-8374) have also incorporated this bis -THF ligand and demonstrated marked antiviral potency against a panel of multidrug-resistant HIV-1 variants. 6,7 …”

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confidence: 99%

Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors

Ghosh

Martyr

Steffey

et al. 2011

ACS Med. Chem. Lett.

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We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions in the HIV-1 protease active site. In this context, we have carried out convenient syntheses of optically active bis-THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV-1 protease inhibitors. Inhibitor 23c turned out to be the most potent (Ki = 2.9 pM; IC50 = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site.

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Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: The discovery of GW0385

Cited by 75 publications

References 19 publications

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

Computational Investigation of the Oxidative Deboronation of Boroglycine, H₂N−CH₂−B(OH)₂, Using H₂O and H₂O₂

Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors

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Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: The discovery of GW0385

Cited by 75 publications

References 19 publications

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

Computational Investigation of the Oxidative Deboronation of Boroglycine, H2N−CH2−B(OH)2, Using H2O and H2O2

Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors

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Computational Investigation of the Oxidative Deboronation of Boroglycine, H₂N−CH₂−B(OH)₂, Using H₂O and H₂O₂