Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor

Neelamkavil, Santhosh; Agrawal, Sony; Bara, Thomas; Bennett, Chad E.; Bhat, Sathesh; Biswas, D.; Brockunier, Linda; Buist, Nicole; Burnette, Duane; Cartwright, Mark E.; Chackalamannil, Samuel; Chase, Robert A.; Chelliah, Mariappan V.; Chen, Austin; Clasby, Martin C.; Colandrea, Vincent J.; Davies, Ian W.; Eagen, Keith; Guo, Zhuyan; Han, Yongxin; Howe, John A.; Jayne, Charles; Josien, Hubert; Kargman, Stacia; Marcantonio, Karen; Miao, Shouwu; Miller, Ross A.; Nolting, Andrew; Pinto, Patrick; Rajagopalan, Murali; Ruck, Rebecca T.; Shah, Unmesh; Soriano, Aileen; Sperbeck, Donald M.; Velázquez, Francisco; Jin, Wei; Yan, Xiaofeng; Venkatraman, Srikanth

doi:10.1021/acsmedchemlett.5b00425

Cited by 31 publications

(24 citation statements)

References 17 publications

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“…The spirocyclic feature in 6 was present in a member of a compound library screened for antibacterial activity. Macrocyclic spirocycle 7 is an inhibitor of the hepatitis C virus (HCV)-NS3/4a protease and is structurally related to other macrocyclic inhibitors of this enzyme such as danoprevir [16].…”

Section: Spirocyclic Examplesmentioning

confidence: 99%

The utilization of spirocyclic scaffolds in novel drug discovery

Zheng¹,

Tice²

2016

Expert Opinion on Drug Discovery

192

139

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Section: Spirocyclic Examplesmentioning

confidence: 99%

The utilization of spirocyclic scaffolds in novel drug discovery

Zheng¹,

Tice²

2016

Expert Opinion on Drug Discovery

192

139

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“…MK-8831 -MK-8831 (Fig. 2) with a novel spiro-proline macrocycle is a follow-up compound of MK-5172 (Neelamkavil et al, 2016). Based on rational computational modeling and structureguided designs, MK-8831 was found to offer robust pangenotypic activity and good coverage of NS3/4A resistant strains (Neelamkavil et al, 2016).…”

Section: Ns3/4a Inhibitorsmentioning

confidence: 99%

Current therapy for chronic hepatitis C: The role of direct-acting antivirals

2017

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One of the most exciting developments in antiviral research has been the discovery of the direct-acting antivirals (DAAs) that effectively cure chronic hepatitis C virus (HCV) infections. Based on more than 100 clinical trials and real-world studies, we provide a comprehensive overview of FDA-approved therapies and newly discovered anti-HCV agents with a special focus on drug efficacy, mechanisms of action, and safety. We show that HCV drug development has advanced in multiple aspects: (i) interferon-based regimens were replaced by interferon-free regimens; (ii) genotype-specific drugs evolved to drugs for all HCV genotypes; (iii) therapies based upon multiple pills per day were simplified to a single pill per day; (iv) drug potency increased from moderate (∼60%) to high (>90%) levels of sustained virologic responses; (v) treatment durations were shortened from 48 to 12 or 8 weeks; and (vi) therapies could be administered orally regardless of prior treatment history and cirrhotic status. However, despite these remarkable achievements made in HCV drug discovery, challenges remain in the management of difficult-to-treat patients.

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confidence: 99%

“…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.…”

mentioning

confidence: 99%

“…The successful investigation of this hypothesis was extensively described in our previous communication. 10 While the clinical evaluation of MK-5172 (grazoprevir) and MK-8831 was ongoing, we envisioned a new class of HCV protease inhibitors resulting from the hybridization of the structural motifs present in each of the clinical candidates. Thus, combination of the P2−P4 macrocyclic ring of MK-5172 (grazoprevir) with the spirocyclic proline of MK-8831 led to an unprecedented class of molecules such as 4 as depicted in Figure 2.…”

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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 MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor

Cited by 31 publications

References 17 publications

The utilization of spirocyclic scaffolds in novel drug discovery

The utilization of spirocyclic scaffolds in novel drug discovery

Current therapy for chronic hepatitis C: The role of direct-acting antivirals

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

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