P3-P4 ureas and reverse carbamates as potent HCV NS3 protease inhibitors: Effective transposition of the P4 hydrogen bond donor

Venables, Brian L.; Sin, Nancy L.; Wang, Alan Xiangdong; Sun, Li‐Qiang; Tu, Yong; Hernandez, Dennis; Sheaffer, Amy K.; Lee, Min; Dunaj, Cindy; Zhai, Guangzhi; Barry, Diana; Friborg, Jacques; Yu, Fei; Knipe, Jay O.; Sandquist, Jason; Falk, Paul; Parker, Dawn D.; Good, Andrew C.; Rajamani, Ramkumar; McPhee, Fiona; Meanwell, Nicholas A.; Scola, Paul M.

doi:10.1016/j.bmcl.2018.04.009

Cited by 7 publications

(12 citation statements)

References 26 publications

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“…In particular, the D168A mutation occurs frequently in viruses that have been treated with inhibitors that bind to S 2 or an adjacent S 4 patch. This mutation reduces the efficacy of drugs such as the linear inhibitor (asunaprevir) P 1 –P 3 macrocyclic compounds (danoprevir, simeprevir, and paritaprevir), and P 2 –P 4 macrocyclic compounds (vaniprevir and grazoprevir). − …”

Section: Results and Discussionmentioning

confidence: 99%

“…The first NS3/4A HCV protease inhibitors, boceprevir and telaprevir, approved in 2011, were prescribed to patients with genotype 1 (GT1) viral strain along with pegylated interferon alpha (PEG-IFN∝) and ribavirin. A second generation of orally available NS3/4 HCV protease inhibitor simeprevir (Olysio, Sovriad) and nucleoside analogue NS5B polymerase inhibitor sofosbuvir (Sovaldi) received FDA approval in 2013. , Between 2013 and 2016, several noncovalent peptidomimetic protease inhibitors including linear (asunaprevir), P 1 –P 3 macrocyclic compounds (danoprevir, simeprevir, and paritaprevir), and P 2 –P 4 macrocyclic compounds (vaniprevir and grazoprevir) were also approved in combination with NS5A interferon resistance inhibitor and/or NS5B polymerase inhibitor. − For these inhibitors, P 1 , P 2 , P 3 , and P 4 correspond to the substrate amino acid side-chain equivalents in the inhibitor that interact with the S 1 , S 2 , S 3 , and S 4 substrate binding pockets of the protease, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of New Inhibitors of Hepatitis C Virus NS3/4A Protease and Its D168A Mutant

Meewan¹,

Zhang²,

Roy³

et al. 2019

ACS Omega

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Hepatitis C virus (HCV) is a human pathogen with high morbidity. The HCV NS3/4A protease is essential for viral replication and is one of the top three drug targets. Several drugs targeting the protease have been developed, but drug-resistant mutant strains emerged. Here, we screened a library and synthesized a novel class of small molecules based on a tryptophan derivative scaffold identified as HCV NS3/4A protease inhibitors that are active against both wild type and mutant form of the protease. Only the compounds with predicted binding poses not affected by the most frequent mutations in the active site were selected for experimental validation. The antiviral activities were evaluated by replicon and enzymatic assays. Twenty-two compounds were found to inhibit HCV with EC50 values ranging between 0.64 and 63 μM with compound 22 being the most active. In protease assays, 22 had a comparable inhibition profile for the common mutant HCV GT1b D168A and the wild-type enzyme. However, in the same assay, the potency of the approved drug, simeprevir, decreased 5.7-fold for the mutant enzyme relative to the wild type. The top three inhibitors were also tested against four human serine proteases and were shown to be specific to the viral protease. The fluorescence-based cell viability assay demonstrated a sufficient therapeutic range for the top three candidates.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of New Inhibitors of Hepatitis C Virus NS3/4A Protease and Its D168A Mutant

Meewan¹,

Zhang²,

Roy³

et al. 2019

ACS Omega

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“…22−24 Acylureas and acylthioureas contain two NH groups, which are also highly susceptible to additional hydrogen bonds with the target protein. 25,26 With this characteristic in mind, we speculated whether the insecticidal activity could be enhanced by forming additional hydrogen bonds through the introduction of acylurea and acylthiourea moieties. Herein, as a continuation of our work and to verify our hypothesis, a series of novel acylurea and acylthiourea derivatives were rationally designed and synthesized by replacing the hydroxyl group at the C4″ position with acylurea and acylthiourea active groups (Figure 1).…”

Section: ■ Introductionmentioning

confidence: 99%

“…In fact, Tomizawa and Yamamoto, Kagabu and Matsuno, Casida and co-workers, and Qian and co-workers demonstrated the importance of the hydrogen bond between pesticide molecules and target proteins in various modes. To the best of our knowledge, use of acylureas and acylthioureas has been reported for many years in insecticidal, herbicidal, and fungicidal applications for crop protection. − Acylureas and acylthioureas contain two NH groups, which are also highly susceptible to additional hydrogen bonds with the target protein. , With this characteristic in mind, we speculated whether the insecticidal activity could be enhanced by forming additional hydrogen bonds through the introduction of acylurea and acylthiourea moieties.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Insecticidal Activity of Novel Doramectin Derivatives Containing Acylurea and Acylthiourea Based on Hydrogen Bonding

Zhang

Cheng

Zheng

et al. 2020

J. Agric. Food Chem.

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Our recent investigation on the insecticidal activities of several doramectin derivatives preliminarily revealed that the presence of hydrogen bonds at the C4″ position of the molecule with target protein γ-aminobutyric acid (GABA) receptor was crucial for retaining high insecticidal activity. As a continuation of our research work on the development of new insecticides, two series of novel acylurea and acylthiourea doramectin derivatives were designed and synthesized. The bioassay results indicated that the newly synthesized compounds (5o, 5t, and 6t) exhibited higher insecticidal activity against diamondback moth, oriental armyworm, and corn borer than the control compounds doramectin, commercial avermectins, chlorbenzuron, and lead compound 3g in our laboratory. Specifically, compound 5t was identified as the most promising insecticide against diamondback moth, with a final mortality rate of 80.00% at the low concentration of 12.50 mg/L, showing approximately 7.75-fold higher potency than the parent doramectin (LC50 value of 48.1547 mg/L), 6.52-fold higher potency than commercial avermectins (LC50 value of 40.5507 mg/L), and 3.98-fold higher potency than compound 3g (LC50 value of 24.7742 mg/L). Additionally, molecular docking simulations revealed that compound 5t (2.17, 2.20, 2.56, and 2.83 Å) displayed stronger hydrogen-bond action in binding with the GABA receptor, better than that of compound 5o (1.64 and 2.15 Å) and compound 6t (2.20 and 2.31 Å) at the C4″ position. This work demonstrated that these compounds containing hydrogen-bond groups might contribute to the improvement of insecticidal activity and supply certain hints toward structure optimization design for the development of new insecticides.

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“…However, this reduction in molecular weight resulted in an inferior in vivo profile, with both the plasma and, particularly, the liver exposure significantly reduced after ID dosing compared to 11. Further molecular modification of P 4 in the context of the urea 21, reverse carbamate 22, the isopropyl carbamate 23, and the cyclopentyl carbamate 24 led to additional insightful and interesting SAR points, but none provided the kind of in vivo profile that was considered to be promising, with plasma and liver exposures in the 4-h rat experiment less than that observed for 11 [26,38]. The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease.…”

Section: Introductionmentioning

confidence: 99%

The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032)

Meanwell¹,

Rajamani²,

Scola³

et al. 2019

Topics in Medicinal Chemistry

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The discovery of asunaprevir (1) began with the concept of engaging the small and well-defined S 1 ' pocket of the hepatitis C virus (HCV) NS3/4A protease that was explored in the context of tripeptide carboxylic acid-based inhibitors. A cyclopropyl-acyl sulfonamide moiety was found to be the optimal element at the P 1-P 1 ' interface enhancing the potency of carboxylic acid-based prototypes by 10-to >100-fold, dependent upon the specific background. Optimization for oral bioavailability identified a 1-substituted isoquinoline-based P 2 * element that conferred a significant exposure advantage in rats compared to the matched 4-substituted quinoline isomer. BMS-605339 (30) was the first cyclopropyl-acyl sulfonamide derivative advanced into clinical trials that demonstrated dose-related reductions in plasma viral RNA in HCV-infected patients. However, 30 was

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P3-P4 ureas and reverse carbamates as potent HCV NS3 protease inhibitors: Effective transposition of the P4 hydrogen bond donor

Cited by 7 publications

References 26 publications

Discovery of New Inhibitors of Hepatitis C Virus NS3/4A Protease and Its D168A Mutant

Discovery of New Inhibitors of Hepatitis C Virus NS3/4A Protease and Its D168A Mutant

Design, Synthesis, and Insecticidal Activity of Novel Doramectin Derivatives Containing Acylurea and Acylthiourea Based on Hydrogen Bonding

The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032)

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