The Experts below are selected from a list of 1977 Experts worldwide ranked by ideXlab platform
Wensheng Yu - One of the best experts on this subject based on the ideXlab platform.
-
discovery of novel pan genotypic hcv NS5A Inhibitors containing a novel tetracyclic core
Bioorganic & Medicinal Chemistry Letters, 2019Co-Authors: Wensheng Yu, Bin Hu, Bin Zhong, Sony Agrawal, Laura Rokosz, Shiying Chen, Ernest Asanteappiah, Joseph A KozlowskiAbstract:Abstract A series of novel tetracyclic core-containing HCV NS5A Inhibitors has been discovered. Incorporation of tetrahydropyran-substituted amino acid moiety improved their potency and yielded HCV NS5A Inhibitors with a minimum potency shift from the GT1a strain compared to other genotypes and mutants. Compounds 53 and 54 showed the best potency profile and had reasonable half-times in rat PK studies. However, further optimization of their oral bioavailability is still needed in order to advance them for further development. [BMCL ABSTRACT] ©2000 Elsevier Science Ltd. All rights reserved.
-
Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms.
Journal of Medicinal Chemistry, 2016Co-Authors: Ling Tong, Wensheng Yu, Oleg Selyutin, Lei Chen, Michael P Dwyer, Anilkumar G Nair, Robert MazzolaAbstract:We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a “flat” GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole–proline–valine Moc motifs of our previous NS5A Inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.
-
discovery of chromane containing hepatitis c virus hcv NS5A Inhibitors with improved potency against resistance associated variants
Journal of Medicinal Chemistry, 2016Co-Authors: Wensheng Yu, Craig A Coburn, Oleg Selyutin, Tao Ji, Ling Tong, Lei Chen, Bin Hu, Bin Zhong, Laura Rokosz, Sony AgrawalAbstract:The discovery of potent and pan-genotypic HCV NS5A Inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, we now describe the discovery of a novel series of chromane containing NS5A Inhibitors. SAR studies around the “Z” group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the phenyl group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivatives as “Z” group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A Inhibitors, such as compounds 14 and 25–28, with significantly improved potency ag...
-
structure activity relationships of proline modifications around the tetracyclic indole class of NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Craig A Coburn, Oleg Selyutin, Lei Chen, Qingbei Zeng, Michael P Dwyer, Anilkumar G Nair, Bandarpalle B Shankar, Deyi YangAbstract:Abstract We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) Inhibitors, to their replicon profiles. This work identified NS5A Inhibitors with an improved and flattened resistance profiles.
-
alternative core development around the tetracyclic indole class of hcv NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Stuart B Rosenblum, Craig A Coburn, Oleg Selyutin, Lei Chen, Michael P Dwyer, Anilkumar G Nair, Peter T Meinke, Yueheng JiangAbstract:Abstract Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) Inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core.
Michael P Dwyer - One of the best experts on this subject based on the ideXlab platform.
-
MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV.
Bioorganic & Medicinal Chemistry Letters, 2018Co-Authors: Anilkumar G Nair, Stuart B Rosenblum, Oleg Selyutin, Qingbei Zeng, Deyi Yang, Yueheng Jiang, Kerry M Keertikar, Guowei Zhou, Michael P DwyerAbstract:Abstract HCV NS5A Inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.
-
Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms.
Journal of Medicinal Chemistry, 2016Co-Authors: Ling Tong, Wensheng Yu, Oleg Selyutin, Lei Chen, Michael P Dwyer, Anilkumar G Nair, Robert MazzolaAbstract:We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a “flat” GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole–proline–valine Moc motifs of our previous NS5A Inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.
-
structure activity relationships of proline modifications around the tetracyclic indole class of NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Craig A Coburn, Oleg Selyutin, Lei Chen, Qingbei Zeng, Michael P Dwyer, Anilkumar G Nair, Bandarpalle B Shankar, Deyi YangAbstract:Abstract We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) Inhibitors, to their replicon profiles. This work identified NS5A Inhibitors with an improved and flattened resistance profiles.
-
alternative core development around the tetracyclic indole class of hcv NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Stuart B Rosenblum, Craig A Coburn, Oleg Selyutin, Lei Chen, Michael P Dwyer, Anilkumar G Nair, Peter T Meinke, Yueheng JiangAbstract:Abstract Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) Inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core.
-
Structure–activity relationships of proline modifications around the tetracyclic-indole class of NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Craig A Coburn, Oleg Selyutin, Lei Chen, Qingbei Zeng, Michael P Dwyer, Anilkumar G Nair, Bandarpalle B ShankarAbstract:Abstract We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) Inhibitors, to their replicon profiles. This work identified NS5A Inhibitors with an improved and flattened resistance profiles.
Deyi Yang - One of the best experts on this subject based on the ideXlab platform.
-
MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV.
Bioorganic & Medicinal Chemistry Letters, 2018Co-Authors: Anilkumar G Nair, Stuart B Rosenblum, Oleg Selyutin, Qingbei Zeng, Deyi Yang, Yueheng Jiang, Kerry M Keertikar, Guowei Zhou, Michael P DwyerAbstract:Abstract HCV NS5A Inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.
-
structure activity relationships of proline modifications around the tetracyclic indole class of NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Craig A Coburn, Oleg Selyutin, Lei Chen, Qingbei Zeng, Michael P Dwyer, Anilkumar G Nair, Bandarpalle B Shankar, Deyi YangAbstract:Abstract We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) Inhibitors, to their replicon profiles. This work identified NS5A Inhibitors with an improved and flattened resistance profiles.
-
matched and mixed cap derivatives in the tetracyclic indole class of hcv NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Michael P Dwyer, Wensheng Yu, Oleg Selyutin, Ling Tong, Lei Chen, Anilkumar G Nair, Kerry M Keertikar, Guowei Zhou, Brian J Lavey, Deyi YangAbstract:A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A Inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.
-
discovery of fused tricyclic core containing hcv NS5A Inhibitors with pan genotype activity
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Wensheng Yu, Stuart B Rosenblum, Craig A Coburn, Michael Wong, Lei Chen, Deyi Yang, Peter T Meinke, Kevin X Chen, George F Njoroge, Michael P DwyerAbstract:Abstract HCV NS5A Inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A Inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.
-
Alkyl substituted aminal derivatives of HCV NS5A inhibitor MK-8742.
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Wensheng Yu, Craig A Coburn, Michael Wong, Ling Tong, Michael P Dwyer, Anilkumar G Nair, Bin Hu, Bin Zhong, Deyi YangAbstract:Abstract HCV NS5A Inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein we describe our continued research efforts around the alkyl “Z group” modification of the tetracyclic indole-based NS5A inhibitor MK-8742, which led to the discovery of a series of potent NS5A Inhibitors. Compounds 10 and 19 are of particular interests since they are as potent as our previous leads and have much improved rat pharmacokinetic profiles.
Oleg Selyutin - One of the best experts on this subject based on the ideXlab platform.
-
MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV.
Bioorganic & Medicinal Chemistry Letters, 2018Co-Authors: Anilkumar G Nair, Stuart B Rosenblum, Oleg Selyutin, Qingbei Zeng, Deyi Yang, Yueheng Jiang, Kerry M Keertikar, Guowei Zhou, Michael P DwyerAbstract:Abstract HCV NS5A Inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.
-
Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms.
Journal of Medicinal Chemistry, 2016Co-Authors: Ling Tong, Wensheng Yu, Oleg Selyutin, Lei Chen, Michael P Dwyer, Anilkumar G Nair, Robert MazzolaAbstract:We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a “flat” GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole–proline–valine Moc motifs of our previous NS5A Inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.
-
discovery of chromane containing hepatitis c virus hcv NS5A Inhibitors with improved potency against resistance associated variants
Journal of Medicinal Chemistry, 2016Co-Authors: Wensheng Yu, Craig A Coburn, Oleg Selyutin, Tao Ji, Ling Tong, Lei Chen, Bin Hu, Bin Zhong, Laura Rokosz, Sony AgrawalAbstract:The discovery of potent and pan-genotypic HCV NS5A Inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, we now describe the discovery of a novel series of chromane containing NS5A Inhibitors. SAR studies around the “Z” group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the phenyl group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivatives as “Z” group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A Inhibitors, such as compounds 14 and 25–28, with significantly improved potency ag...
-
structure activity relationships of proline modifications around the tetracyclic indole class of NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Craig A Coburn, Oleg Selyutin, Lei Chen, Qingbei Zeng, Michael P Dwyer, Anilkumar G Nair, Bandarpalle B Shankar, Deyi YangAbstract:Abstract We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) Inhibitors, to their replicon profiles. This work identified NS5A Inhibitors with an improved and flattened resistance profiles.
-
alternative core development around the tetracyclic indole class of hcv NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Stuart B Rosenblum, Craig A Coburn, Oleg Selyutin, Lei Chen, Michael P Dwyer, Anilkumar G Nair, Peter T Meinke, Yueheng JiangAbstract:Abstract Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) Inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core.
Anilkumar G Nair - One of the best experts on this subject based on the ideXlab platform.
-
MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV.
Bioorganic & Medicinal Chemistry Letters, 2018Co-Authors: Anilkumar G Nair, Stuart B Rosenblum, Oleg Selyutin, Qingbei Zeng, Deyi Yang, Yueheng Jiang, Kerry M Keertikar, Guowei Zhou, Michael P DwyerAbstract:Abstract HCV NS5A Inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.
-
Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms.
Journal of Medicinal Chemistry, 2016Co-Authors: Ling Tong, Wensheng Yu, Oleg Selyutin, Lei Chen, Michael P Dwyer, Anilkumar G Nair, Robert MazzolaAbstract:We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a “flat” GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole–proline–valine Moc motifs of our previous NS5A Inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.
-
structure activity relationships of proline modifications around the tetracyclic indole class of NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Craig A Coburn, Oleg Selyutin, Lei Chen, Qingbei Zeng, Michael P Dwyer, Anilkumar G Nair, Bandarpalle B Shankar, Deyi YangAbstract:Abstract We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) Inhibitors, to their replicon profiles. This work identified NS5A Inhibitors with an improved and flattened resistance profiles.
-
alternative core development around the tetracyclic indole class of hcv NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Stuart B Rosenblum, Craig A Coburn, Oleg Selyutin, Lei Chen, Michael P Dwyer, Anilkumar G Nair, Peter T Meinke, Yueheng JiangAbstract:Abstract Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) Inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core.
-
Structure–activity relationships of proline modifications around the tetracyclic-indole class of NS5A Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Ling Tong, Wensheng Yu, Craig A Coburn, Oleg Selyutin, Lei Chen, Qingbei Zeng, Michael P Dwyer, Anilkumar G Nair, Bandarpalle B ShankarAbstract:Abstract We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) Inhibitors, to their replicon profiles. This work identified NS5A Inhibitors with an improved and flattened resistance profiles.
