Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors

Vendeville, Sandrine; Nilsson, Magnus; Kock, Herman de; Lin, Tse‐I; Antonov, D. M.; Classon, Björn; Ayesa, Susana; Иванов, В. Л.; Johansson, Per-Ola; Kahnberg, Pia; Eneroth, Anders; Wikström, Kristina; Vrang, Lotta; Edlund, Michael; Lindström, Stefan B.; Vreken, Wim Van de; McGowan, David; Tahri, Abdellah; Hu, Lili; Lenz, Oliver; Delouvroy, Frédéric; Dooren, Marleen Van; Kindermans, Natalie; Surleraux, Dominique; Wigerinck, Piet; Rosenquist, Åsa; Samuelsson, Bertil; Simmen, Kenneth; Raboisson, Pierre

doi:10.1016/j.bmcl.2008.10.004

Cited by 22 publications

(12 citation statements)

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“…Non-charged inhibitors include a series of 8-hydroxyquinoline [19] , some uncompetitive inhibitors [18] , and 15 inhibitors reported in PubChem BioAssay database [20] . Inhibitors for the close related NS3 proteases of Hepatitis C, dengue, and yellow fever virus have also been identified [8] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] . In this paper, we report the discovery of a WNV protease inhibitor by our in silico high-throughput screening approach and experimental validations.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking

Ekonomiuk

Ozawa

et al. 2009

PLoS Negl Trop Dis

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BackgroundThe non-structural 3 protease (NS3pro) is an essential flaviviral enzyme and therefore one of the most promising targets for drug development against West Nile virus (WNV) and dengue infections.MethodologyIn this work, a small-molecule inhibitor of the WNV NS3pro has been identified by automatic fragment-based docking of about 12000 compounds and testing by nuclear magnetic resonance (NMR) spectroscopy of only 22 molecules. Specific binding of the inhibitor into the active site of NS3pro and its binding mode are confirmed by 15N-HSQC NMR spectra. The inhibitory activity is further validated by an enzymatic assay and a tryptophan fluorescence quenching assay.ConclusionThe inhibitor [4-(carbamimidoylsulfanylmethyl)-2,5-dimethylphenyl]-methylsulfanylmethanimidamide has a good ratio of binding affinity versus molecular weight (ligand efficiency of 0.33 kcal/mol per non-hydrogen atom), and thus has good potential as lead compound for further development to combat West Nile virus infections.

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Section: Introductionmentioning

confidence: 99%

Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking

Ekonomiuk

Ozawa

et al. 2009

PLoS Negl Trop Dis

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“…Extending inhibitors to this untapped region of the protease active site can enhance inhibitor potency. Another strategy that significantly enhanced HCV PI potency is adding a macrocycle to link either the P2–P4 or P1–P3 moieties [55–57]. The macrocycle is thought to stabilize the inhibitor in a conformation competent for protease binding, thus increasing the entropic contribution to the free energy of binding.…”

Section: Increasing Potency To Avoid Resistancementioning

confidence: 99%

Improving Viral Protease Inhibitors to Counter Drug Resistance

Yilmaz

Swanstrom

Schiffer

2016

Trends in Microbiology

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Drug resistance is a major problem in health care, undermining therapy outcomes and necessitating novel approaches to drug design. Extensive studies on resistance to viral protease inhibitors, particularly those of HIV-1 and hepatitis C virus (HCV) protease, revealed a plethora of information on the structural and molecular mechanisms underlying resistance. These insights led to several strategies to improve viral protease inhibitors to counter resistance, such as exploiting the essential biological function and leveraging evolutionary constraints. Incorporation of these strategies into structure-based drug design can minimize vulnerability to resistance, not only for viral proteases but for other quickly evolving drug targets as well, toward designing inhibitors one step ahead of evolution to counter resistance with more intelligent and rational design.

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“…The extensive efforts toward the identification of HCV NS3 protease inhibitors by our research group and others have resulted in a deep understanding of the structural modifications that could positively affect the potency profile of target molecules. It has previously been determined that in some cases the introduction of a methyl group into the cyclopropyl acylsulfonamide-P1′ improved potency and plasma exposure. , Thus, compound 6 was synthesized and had its activity measured. Its enzyme inhibition profile across genotypes and mutants was similar to that of compound 5 .…”

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confidence: 99%

“…It has previously been determined that in some cases the introduction of a methyl group into the cyclopropyl acylsulfonamide-P1′ improved potency and plasma exposure. 11,12 Thus, compound 6 was synthesized and had its activity measured. Its enzyme inhibition profile across genotypes and mutants was similar to that of compound 5.…”

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confidence: 99%

“…Our research group has also reported the identification of P1−P3/P2−P4 bis-macrocycles as viable HCV NS3/4A protease inhibitors. 13,14 MK-6325 (12) represents compounds in this class with an excellent potency profile across genotypes and mutant strains (Figure 4). MK-6325 (12) shares many of the structural features of MK-5172 (grazoprevir) (1) such as the quinoxaline−P2 and the P2−P4 macrocyclic core but it has an additional macrocyclic ring formed by the tethering the P1 and P3 groups.…”

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confidence: 99%

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Design and Synthesis of P2–P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors

Velázquez

Chelliah

Clasby

et al. 2016

ACS Med. Chem. Lett.

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A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline−P2 surrogate onto the P2−P4 macrocyclic core of . The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC 50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia−Kocienski olefination and macrolactamization to assemble the P2−P4 macrocyclic core containing the novel spirocyclic proline−P2 moiety is presented as well. KEYWORDS: Hepatitis C, HCV, HCV NS3/4A, antivirals, MK-5172, H epatitis C is a liver infection caused by the hepatitis C virus (HCV). There is an estimated 130−150 million people infected around the world. 1 In the United States alone 3.2 million people are infected with the virus and the disease will progress to a chronic stage in approximately 75−85% of patients. 2 Since chronic HCV infection is the leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation, the disease represents a major burden for patients and health care systems worldwide. 3,4 The HCV virus was identified more than two decades ago, and its discovery triggered an enormous research effort to identify direct acting antiviral agents capable of curing the disease. The HCV virus is a (+)-strand RNA that encodes a polyprotein of approximately 3000 amino acids, which contains the necessary enzymes for viral replication. The HCV NS3/4A protease is one of those enzymes that plays an essential role in viral replication. 5,6 HCV protease inhibitors were the first direct acting antivirals approved for treatment of the disease and remain an integral component of new combination therapies aiming for all-oral regimens. 7 Our research group reported the discovery of the HCV protease inhibitor MK-5172 (grazoprevir) (1), 8 Figure 1, which has been approved by the United States Food and Drug Administration for the treatment of HCV infection in combination with the HCV 5a inhibitor MK-8742 (elbasvir). MK-5172 (grazoprevir) has proven effective in treating the HCV infection with greater than 95% sustained virologic response (SVR) in patients infected with genotype-1. 9 Due to its impressive clinical results MK-5172 received "breakthrough therapy" designation by the FDA prior to its approval. More recently, we disclosed the identification of MK-8831 (2), 10 Figure 1, which represents a new class of HCV NS3/4A inhibitors containing a unique "spirocyclic" proline as P2-surrogate. MK-8831 was advanced to clinical trials to assess its efficacy.The unique "spirocyclic" proline present in MK-8831 was designed to reduce the entropic cost of binding of inhibitors having an ether-linked biaryl group attached to the P2-proline such as grazoprevir, paritaprevir, simeprivir (a cyclopentane ring replaces the P2-proline in simeprivir), and others. An improvement in potency was expected by rigidifying th...

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Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors

Cited by 22 publications

References 19 publications

Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking

Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking

Improving Viral Protease Inhibitors to Counter Drug Resistance

Design and Synthesis of P2–P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors

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