Kevin X Chen

Summary

Affiliation: Schering-Plough Research Institute
Country: USA

Publications

  1. ncbi Syntheses of novel 4-tert-alkyl ether proline-based 16- and 17-membered macrocyclic compounds
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, NJ 07033, USA
    J Org Chem 67:2730-3. 2002
  2. ncbi A review of HCV protease inhibitors
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
    Curr Opin Investig Drugs 10:821-37. 2009
  3. doi Second-generation highly potent and selective inhibitors of the hepatitis C virus NS3 serine protease
    Kevin X Chen
    Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA
    J Med Chem 52:1370-9. 2009
  4. doi Novel potent inhibitors of hepatitis C virus (HCV) NS3 protease with cyclic sulfonyl P3 cappings
    Kevin X Chen
    Infectious Disease Tumor Biology, Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 A 3545, Kenilworth, NJ 07033, USA
    Bioorg Med Chem Lett 19:1105-9. 2009
  5. ncbi Potent and selective small molecule NS3 serine protease inhibitors of Hepatitis C virus with dichlorocyclopropylproline as P2 residue
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, NJ 07033, USA
    Bioorg Med Chem 16:1874-83. 2008
  6. ncbi Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycles
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, NJ 07033, USA
    J Med Chem 49:995-1005. 2006
  7. ncbi Potent 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid-based macrocyclic inhibitors of hepatitis C virus NS3 protease
    Kevin X Chen
    Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA
    J Med Chem 49:567-74. 2006
  8. ncbi Proline-based macrocyclic inhibitors of the hepatitis C virus: stereoselective synthesis and biological activity
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, NJ 07033, USA
    Angew Chem Int Ed Engl 44:7024-8. 2005
  9. ncbi Design, synthesis, and biological activity of m-tyrosine-based 16- and 17-membered macrocyclic inhibitors of hepatitis C virus NS3 serine protease
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, New Jersey 07033, USA
    J Med Chem 48:6229-35. 2005
  10. ncbi Synthesis and biological activity of macrocyclic inhibitors of hepatitis C virus (HCV) NS3 protease
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, NJ 07033, USA
    Bioorg Med Chem Lett 15:4475-8. 2005

Collaborators

Detail Information

Publications25

  1. ncbi Syntheses of novel 4-tert-alkyl ether proline-based 16- and 17-membered macrocyclic compounds
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, NJ 07033, USA
    J Org Chem 67:2730-3. 2002
    ..The macrocyclization of 2 was accomplished through a Mitsunobu reaction using triphenylphosphine and 1,1'-(azodicarbonyl)dipiperidine (ADDP), to afford novel 16- and 17-membered proline-based macrocyclic compounds of type 3...
  2. ncbi A review of HCV protease inhibitors
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
    Curr Opin Investig Drugs 10:821-37. 2009
    ..This review focuses on the recent advances in the development of HCV protease inhibitors...
  3. doi Second-generation highly potent and selective inhibitors of the hepatitis C virus NS3 serine protease
    Kevin X Chen
    Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA
    J Med Chem 52:1370-9. 2009
    ..X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159...
  4. doi Novel potent inhibitors of hepatitis C virus (HCV) NS3 protease with cyclic sulfonyl P3 cappings
    Kevin X Chen
    Infectious Disease Tumor Biology, Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 A 3545, Kenilworth, NJ 07033, USA
    Bioorg Med Chem Lett 19:1105-9. 2009
    ..This compound had the best overall profile in potency and PK profile: excellent K(i)(*) of 5.3 nM and activity in replicon (EC(90)) of 80 nM, extremely high selectivity of 6100, and a good rat PO AUC of 1.43 microMh...
  5. ncbi Potent and selective small molecule NS3 serine protease inhibitors of Hepatitis C virus with dichlorocyclopropylproline as P2 residue
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, NJ 07033, USA
    Bioorg Med Chem 16:1874-83. 2008
    ..Its bioavailabilities were above 10% in all three animal species (rats, monkeys, and dogs). It has provided a lead for future investigations...
  6. ncbi Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycles
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, NJ 07033, USA
    J Med Chem 49:995-1005. 2006
    ..The strategy of macrocyclization has been proved to be successful in improving potency (>20-fold greater than that of 1) and in structural depeptization...
  7. ncbi Potent 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid-based macrocyclic inhibitors of hepatitis C virus NS3 protease
    Kevin X Chen
    Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA
    J Med Chem 49:567-74. 2006
    ..The ketone carbonyl formed a reversible covalent bond with Ser139. The n-propyl of P1 novaline and the aromatic ring of P2' phenylglycine formed a C-shaped clamp around the Lys136 side chain...
  8. ncbi Proline-based macrocyclic inhibitors of the hepatitis C virus: stereoselective synthesis and biological activity
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, NJ 07033, USA
    Angew Chem Int Ed Engl 44:7024-8. 2005
  9. ncbi Design, synthesis, and biological activity of m-tyrosine-based 16- and 17-membered macrocyclic inhibitors of hepatitis C virus NS3 serine protease
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, New Jersey 07033, USA
    J Med Chem 48:6229-35. 2005
    ..P2' phenyl and P1 propyl groups wrapped around the Lys136 side chain, forming a "C"-shaped clamp. The 17-membered macrocyclic inhibitors 17-19 were significantly more potent than the acyclic pentapeptide 1...
  10. ncbi Synthesis and biological activity of macrocyclic inhibitors of hepatitis C virus (HCV) NS3 protease
    Kevin X Chen
    Schering Plough Research Institute, 2015 Galloping Hill Road, K 15 3 3545, Kenilworth, NJ 07033, USA
    Bioorg Med Chem Lett 15:4475-8. 2005
    ..The macrocyclic alpha-ketoamides were active inhibitors of the HCV NS3 protease, with the C-terminal acids and amides being more potent than tert-butyl esters...
  11. doi A novel class of highly potent irreversible hepatitis C virus NS5B polymerase inhibitors
    Kevin X Chen
    Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA
    J Med Chem 55:2089-101. 2012
    ..The overall excellent profile of 47 made it an interesting candidate for further investigation...
  12. doi Toward the back-up of boceprevir (SCH 503034): discovery of new extended P4-capped ketoamide inhibitors of hepatitis C virus NS3 serine protease with improved potency and pharmacokinetic profiles
    Stephane L Bogen
    Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA
    J Med Chem 52:3679-88. 2009
    ..In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P(4)-capped inhibitors were also found to have improved PK profile...
  13. doi Structure-activity relationship (SAR) development and discovery of potent indole-based inhibitors of the hepatitis C virus (HCV) NS5B polymerase
    Kevin X Chen
    Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
    J Med Chem 55:754-65. 2012
    ..02 μM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 μM·h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported...
  14. doi II. Novel HCV NS5B polymerase inhibitors: discovery of indole C2 acyl sulfonamides
    Gopinadhan N Anilkumar
    Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
    Bioorg Med Chem Lett 22:713-7. 2012
    ..Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039μM, replicon EC(50)=0.011μM) with >100-fold improved replicon activity...
  15. doi P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile
    Latha G Nair
    Chemical Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
    Bioorg Med Chem Lett 20:567-70. 2010
    ..Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K(i)( *)=15nM, EC 90=70nM) and pharmacokinetic properties (Rat AUC (PO)=3.52microMh) compared to 1...
  16. doi The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir: a change in direction in the search for a second generation HCV NS3 protease inhibitor
    Frank Bennett
    Schering Plough Research Institute, K 15 A 3545, Kenilworth, NJ 07033, USA
    Bioorg Med Chem Lett 20:2617-21. 2010
    ..Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration...
  17. ncbi P2-P4 macrocyclic inhibitors of hepatitis C virus NS3-4A serine protease
    Ashok Arasappan
    Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
    Bioorg Med Chem Lett 16:3960-5. 2006
    ..X-ray structure of inhibitor 38 bound to the protease is discussed...
  18. doi Discovery and structure-activity relationship of P1-P3 ketoamide derived macrocyclic inhibitors of hepatitis C virus NS3 protease
    Srikanth Venkatraman
    Schering Plough Research Institute, K 15, MS 3545, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA
    J Med Chem 52:336-46. 2009
    ..X-ray structure of 52 bound to NS3 protease and biological data are also discussed...
  19. doi Toward second generation hepatitis C virus NS3 serine protease inhibitors: discovery of novel P4 modified analogues with improved potency and pharmacokinetic profile
    Ashok Arasappan
    Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA
    J Med Chem 52:2806-17. 2009
    ..Combining the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed superior potency and very good oral as well as target organ exposure in rats...
  20. doi Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection
    F George Njoroge
    Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA
    Acc Chem Res 41:50-9. 2008
    ..Boceprevir is well tolerated in humans and demonstrated antiviral activity in phase I clinical trials. It is currently in phase II trials. This Account details the complexity and challenges encountered in the drug discovery process...
  21. doi Optimization of potency and pharmacokinetics of tricyclic indole derived inhibitors of HCV NS5B polymerase. Identification of ester prodrugs with improved oral pharmacokinetics
    Srikanth Venkatraman
    Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States Electronic address
    Bioorg Med Chem 22:447-58. 2014
    ..These analogs also demonstrate excellent PK in rats and monkeys when administered as a dimethyl ethyl amino ester prodrug. ..
  22. doi Discovery of an irreversible HCV NS5B polymerase inhibitor
    Qingbei Zeng
    Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
    Bioorg Med Chem Lett 23:6585-7. 2013
    ..The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 μM), highly selective, and safe in in vitro and in vivo assays...
  23. ncbi The role of P-glycoprotein in the pharmacokinetics and tissue distribution of a hepatitis C virus protease inhibitor
    Kevin X Chen
    Schering Plough Research Institute, Kenilworth, NJ 07033, USA
    Drug Metab Lett 3:290-5. 2009
    ..These results suggest that P-gp efflux limits exposure to S5 in the brain and liver, and that the effect is dependent on the route of administration...
  24. ncbi Novel dipeptide macrocycles from 4-oxo, -thio, and -amino-substituted proline derivatives
    Ashok Arasappan
    Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
    J Org Chem 67:3923-6. 2002
    ..Dipeptide macrocycles of type A have been constructed in a versatile manner from the corresponding 4-heteroatom-substituted proline derivatives using an intramolecular Mitsunobu strategy...
  25. doi I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles
    Gopinadhan N Anilkumar
    Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
    Bioorg Med Chem Lett 21:5336-41. 2011
    ..SAR development resulted in leads 7q (NS5B IC(50)=0.032 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and replicon activity...