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

Ghosh, Arun K.; Osswald, Heather L.; Prato, Gary

doi:10.1021/acs.jmedchem.5b01697

Cited by 370 publications

(416 citation statements)

References 196 publications

(555 reference statements)

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“…[1,2] The introduction of these drug regimens using a combination of reverse transcriptase and protease inhibitor drugs dramatically suppressed viral replication, decreased plasma HIV-1 viral loads, and improved CD4 cell counts in HIV-1-infected patients. [3,4] cART has significantly improved the life expectancy of patients who have access to these treatment regimens. There is currently no cure for HIV-1 infection or AIDS.…”

Section: Introductionmentioning

confidence: 99%

Design of Highly Potent, Dual‐Acting and Central‐Nervous‐System‐Penetrating HIV‐1 Protease Inhibitors with Excellent Potency against Multidrug‐Resistant HIV‐1 Variants

et al. 2018

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Herein we report the design, synthesis, X-ray structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor, compound 5 ((3S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl ((2S,3R)-4-((2-(cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)carbamate). Using structure-based design, we incorporated an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2′-ligand, and a 3,5-difluorophenylmethyl group as the P1-ligand. The resulting inhibitor 5 exhibited exceptional HIV-1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC50 values in the picomolar range against a wide panel of highly multidrug-resistant HIV-1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug-resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. We determined a high-resolution X-ray crystal structure of the complex between inhibitor 5 and HIV-1 protease, which provides molecular insight into the unprecedented activity profiles observed.

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Section: Introductionmentioning

confidence: 99%

Design of Highly Potent, Dual‐Acting and Central‐Nervous‐System‐Penetrating HIV‐1 Protease Inhibitors with Excellent Potency against Multidrug‐Resistant HIV‐1 Variants

et al. 2018

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“…1–3 Its utility is particularly notable in the area of design and development of HIV-1 protease inhibitors. 4,5 The development of protease inhibitors (PIs) and their combination with reverse transcriptase inhibitors marked the beginning of a new era of management of HIV infection and AIDS in the late 1990s. 6,7 HIV-1 PIs are a critical component of current combination antiretroviral therapies (ART) which significantly improved life expectancy and mortality rates of HIV/AIDS patients in developing countries.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X-ray Structural Analysis

et al. 2018

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The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands, are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

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“…The synthesis of inhibitors involves the opening of an aminoalkyl epoxide with an appropriate amine followed by the functionalization of the N -terminus with suitable P2 ligands. 2,4 As shown in Figure 2, BACE1 inhibitors containing a 3,5-difluorophenylmethyl side chain as the P1 ligand in a general inhibitor 3 , can be synthesized from tert -butyl-(( S )-1-( S )-oxiran-2yl)-2-phenylethyl carbamate 4 . Enantioselective synthesis of such epoxide is typically carried out with optically active 3,5-difluorophenyl alanine 5 .…”

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confidence: 99%

Highly stereoselective asymmetric aldol routes to tert-butyl-2-(3,5-difluorophenyl)-1-oxiran-2-yl)ethyl)carbamates: Building blocks for novel protease inhibitors

Ghosh

Cárdenas

Brindisi

2017

Tetrahedron Letters

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Enantioselective syntheses of tert-butyl ((S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethyl)carbamate and ((S)-2-(3,5-difluorophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate are described. We utilized asymmetric syn- and anti-aldol reactions to set both stereogenic centers. We investigated ester-derived Ti-enolate aldol reactions as well as Evans’ diastereoselective syn-aldol reaction for these syntheses. We have converted optically active ((S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethyl)carbamate to a potent β-secretase inhibitor.

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

Cited by 370 publications

References 196 publications

Design of Highly Potent, Dual‐Acting and Central‐Nervous‐System‐Penetrating HIV‐1 Protease Inhibitors with Excellent Potency against Multidrug‐Resistant HIV‐1 Variants

Design of Highly Potent, Dual‐Acting and Central‐Nervous‐System‐Penetrating HIV‐1 Protease Inhibitors with Excellent Potency against Multidrug‐Resistant HIV‐1 Variants

Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X-ray Structural Analysis

Highly stereoselective asymmetric aldol routes to tert-butyl-2-(3,5-difluorophenyl)-1-oxiran-2-yl)ethyl)carbamates: Building blocks for novel protease inhibitors

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