Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates

Li, Xianfeng; Zhang, Yongkang; Liu, Yang; Ding, Charles Z.; Zhou, Yasheen; Li, Qun; Plattner, Jacob J.; Baker, Stephen J.; Zhang, Suoming; Kazmierski, Wieslaw M.; Wright, Laura; Smith, Gary K.; Grimes, Richard M.; Crosby, Renae M.; Creech, Katrina L.; Carballo, Luz H.; Slater, Martin J.; Jarvest, Richard L.; Thömmes, Pia; Hubbard, Julia A.; Convery, M.A.; Nassau, Pamela M.; McDowell, William; Skarżyński, T.; Qian, Xuelei; Fan, Dazhong; Liao, Liang; Ni, Zhi‐Jie; Pennicott, Lewis E.; Zou, Wenli; Wright, Jon

doi:10.1016/j.bmcl.2010.08.022

Cited by 34 publications

(19 citation statements)

References 23 publications

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“…Compounds 62 and 63 (Figure 26) are the most promising agents in the series. x-ray crystallography of compound 62 with NS3 protease reveals that Ser-139 in the enzyme active site traps boron in the P1 region of 62 , which confirms the importance of the boron moiety for activity [118]. …”

Section: Therapeutic Applicationsmentioning

confidence: 94%

Boron Chemicals in Diagnosis and Therapeutics

et al. 2013

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Advances in the field of boron chemistry have expanded the application of boron from material use to medicine. Boron-based drugs represent a new class of molecules that possess several biomedical applications including use as imaging agents for both optical and nuclear imaging as well as therapeutic agents with anticancer, antiviral, antibacterial, antifungal and other disease-specific activities. For example, bortezomib (Velcade®), the only drug in clinical use with boron as an active element, was approved in 2003 as a proteasome inhibitor for the treatment of multiple myeloma and non-Hodgkin’s lymphoma. Several other boron-based compounds are in various phases of clinical trials, which illustrates the promise of this approach for medicinal chemists working in the area of boron chemistry. It is expected that in the near future, several boron-containing drugs should become available in the market with better efficacy and potency than existing drugs. This article discusses the current status of the development of boron-based compounds as diagnostic and therapeutic agents in humans.

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Section: Therapeutic Applicationsmentioning

confidence: 94%

Boron Chemicals in Diagnosis and Therapeutics

et al. 2013

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“… 298 Similarly, macrocyclic inhibitor 292 with an α-amino cyclic boronate showed good potency (IC 50 = 43 nM). 299 …”

Section: Carbamate-based Hcv Therapeuticsmentioning

confidence: 99%

Organic Carbamates in Drug Design and Medicinal Chemistry

2015

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The carbamate group is a key structural motif in many approved drugs and prodrugs. There is an increasing use of carbamates in medicinal chemistry and many carbamate derivatives are specifically designed to make drug-target interactions through their carbamate moiety. In this review, we present properties and stabilities of carbamates, reagents and chemical methodologies for the synthesis of carbamates, and recent application of carbamates in drug design and medicinal chemistry.

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“…81 Synthetic macrocycles that interact with oxygen-based active site residues include boron-containing molecules that were designed at Anacor. 82 In this study, a new series of HCV NS3 serine protease inhibitors equipped with a cyclic boronate moiety at the P1 position of an HCV inhibitor scaffold, were developed and characterized by X-ray crystallography (Fig. 19C).…”

Section: Properties Of Macrocyclesmentioning

confidence: 99%