Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group

Bungard, Christopher J.; Williams, Peter; Ballard, Jeanine; Bennett, David Jonathan; Beaulieu, Christian; Bahnck-Teets, Carolyn; Carroll, Steve; Chang, Ronald K.; Dubost, David C.; Fay, John F.; Diamond, Tracy L.; Greshock, Thomas J.; Li, Hao; Holloway, M. Katharine; Felock, Peter J.; Gesell, Jennifer J.; Su, Hua-Poo; Manikowski, Jesse J.; McKay, Daniel J.; Miller, Mike; Xu, Min; Molinaro, Carmela; Moradei, Oscar; Nantermet, Philippe G.; Nadeau, Christian; Sánchez, Rosa I.; Satyanarayana, T.; Shipe, William D.; Singh, Sanjay K.; Truong, Vouy Linh; Vijayasaradhi, Sivalenka; Wiscount, Catherine M.; Vacca, Joseph P.; Crane, Sheldon N.; McCauley, John A.

doi:10.1021/acsmedchemlett.6b00135

Cited by 25 publications

(25 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Diphenylalanine building block substituted with halogens atoms could be found as N‐terminal amino acid of MK‐8718 inhibitor. The synthesis of MK‐8718 as well as halo‐substituted diphenyl alanine was reported by Bungard and co‐workers [45c] …”

Section: Human Immunodeficiency Virus and Hiv Protease Inhibitorsmentioning

confidence: 99%

Amino Acid and Peptide‐Based Antiviral Agents

2021

View full text Add to dashboard Cite

A significant number of antiviral agents used in clinical practice are amino acids, short peptides, or peptidomimetics. Among them, several HIV protease inhibitors (e. g. lopinavir, atazanavir), HCV protease inhibitors (e. g. grazoprevir, glecaprevir), and HCV NS5A protein inhibitors have contributed to a significant decrease in mortality from AIDS and hepatitis. However, there is an ongoing need for the discovery of new antiviral agents and the development of existing drugs; amino acids, both proteinogenic and non‐proteinogenic in nature, serve as convenient building blocks for this purpose. The synthesis of non‐proteinogenic amino acid components of antiviral agents could be challenging due to the need for enantiomerically or diastereomerically pure products. Herein, we present a concise review of antiviral agents whose structures are based on amino acids of both natural and unnatural origin. Special attention is paid to the synthetic aspects of non‐proteinogenic amino acid components of those agents.

show abstract

Section: Human Immunodeficiency Virus and Hiv Protease Inhibitorsmentioning

confidence: 99%

Amino Acid and Peptide‐Based Antiviral Agents

2021

View full text Add to dashboard Cite

show abstract

“…[9,11] Several potent HIV-1 protease inhibitors incorporating elements of novelty have been reported. [17][18][19][20][21] Also, new PIs with interesting active site interactions have been reported. [21,22] In our continuing efforts towards the development of new non-peptidyl HIV-1 PIs, we have been particularly focusing on the design and synthesis of PIs that exert potent antiviral activity against HIV-1 variants highly resistant to current PIdrugs.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and X‐Ray Structural Studies of Potent HIV‐1 Protease Inhibitors Containing C‐4 Substituted Tricyclic Hexahydro‐Furofuran Derivatives as P2 Ligands

et al. 2022

View full text Add to dashboard Cite

The design, synthesis, X-ray structural, and biological evaluation of a series of highly potent HIV-1 protease inhibitors are reported herein. These inhibitors incorporate novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands in combination with a variety of P1 and P2' ligands. The inhibitor with a difluoromethylphenyl P1 ligand and a cyclopropylaminobenzothiazole P2' ligand exhibited the most potent antiviral activity. Also, it maintained potent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The corresponding inhibitor with an enantiomeric ligand was significantly less potent in these antiviral assays. The new P2 ligands were synthesized in optically active form using enzymatic desymmetrization of meso-diols as the key step. To obtain molecular insight, two high-resolution X-ray structures of inhibitor-bound HIV-1 protease were determined and structural analyses have been highlighted.

show abstract

“…29,30,33 More recently, bicyclic piperazine sulfonamide-based new PIs have been reported in which the piperazine NH forms the key interaction with the catalytic aspartates of the HIV-1 protease. 34,35 …”

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

View full text Add to dashboard Cite

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.

show abstract

Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group

Cited by 25 publications

References 21 publications

Amino Acid and Peptide‐Based Antiviral Agents

Amino Acid and Peptide‐Based Antiviral Agents

Design, Synthesis and X‐Ray Structural Studies of Potent HIV‐1 Protease Inhibitors Containing C‐4 Substituted Tricyclic Hexahydro‐Furofuran Derivatives as P2 Ligands

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

Contact Info

Product

Resources

About