John W. Butcher
Merck & Co.
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Featured researches published by John W. Butcher.
Journal of Medicinal Chemistry | 2015
J. Michael Ellis; Michael D. Altman; Alan S. Bass; John W. Butcher; Alan Byford; Anthony Donofrio; Sheila M. Galloway; Andrew M. Haidle; James P. Jewell; Nancy Kelly; Erica Leccese; Sandra Lee; Matthew L. Maddess; J. Richard Miller; Lily Y. Moy; Ekundayo Osimboni; Ryan D. Otte; M. Vijay Reddy; Kerrie Spencer; Binyuan Sun; Stella H. Vincent; Gwendolyn J. Ward; Grace H. C. Woo; Chiming Yang; Hani Houshyar; Alan B. Northrup
Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles.
Archive | 1997
Nigel Liverton; David A. Claremon; John W. Butcher; Mark T. Bilodeau
Journal of Medicinal Chemistry | 1997
Harold G. Selnick; Nigel Liverton; John J. Baldwin; John W. Butcher; David A. Claremon; Jason Matthew Elliott; Roger M. Freidinger; Stella A. King; Brian Libby; Charles J. Mcintyre; David A. Pribush; David C. Remy; Garry R. Smith; Andrew Tebben; Nancy K. Jurkiewicz; Joseph J. Lynch; Joseph J. Salata; Michael C. Sanguinetti; Peter K. S. Siegl; Donald E. Slaughter; Kamlesh P. Vyas
Journal of Medicinal Chemistry | 1990
James B. Doherty; Bonnie M. Ashe; Peter L. Barker; Blacklock Tj; John W. Butcher; Chandler Go; Mary Ellen Dahlgren; Philip Davies; Conrad P. Dorn; Paul E. Finke
Journal of Organic Chemistry | 1993
Thomas J. Blacklock; Paul Sohar; John W. Butcher; Theresa R. Lamanec; Edward J. J. Grabowski
Journal of Pharmacology and Experimental Therapeutics | 1994
Joseph J. Lynch; Audrey A. Wallace; R. F. Stupienski; E. P. Baskin; C. M. Beare; S. D. Appleby; Joseph J. Salata; Nancy K. Jurkiewicz; Michael C. Sanguinetti; R. B. Stein; J. R. Gehret; T. Kothstein; David A. Claremon; Jason Matthew Elliott; John W. Butcher; David C. Remy; John J. Baldwin
Archive | 2007
Steven Harper; Vincenzo Summa; Nigel Liverton; John A. McCauley; John W. Butcher; Marcello Di Filippo; Maria Emilia Di Francesco; Marco Ferrara; Joseph J. Romano; Michael T. Rudd
Journal of Organic Chemistry | 1988
Thomas J. Blacklock; Richard F. Shuman; John W. Butcher; Willard E. Shearin; John Budavari; Victor J. Grenda
Journal of Organic Chemistry | 1989
Thomas J. Blacklock; John W. Butcher; Paul Sohar; Theresa R. Lamanec; Edward J. J. Grabowski
Archive | 2004
Wayne J. Thompson; Steven D. Young; Brian T. Phillips; Peter M. Munson; Willie L. Whitter; Nigel Liverton; Christine M. Dieckhaus; John W. Butcher; John A. McCauley; Charles J. Mcintyre; Mark E. Layton; Philip E. Sanderson