title: Overcoming mutagenicity and ion channel activity: optimization of selective spleen tyrosine kinase inhibitors.
abstract: 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.
authors.affiliation: Department of Discovery Chemistry, ‡Department of Process Research, §Department of Immunology, ∥Department of Pharmacology, ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Department of Safety Assessment and Laboratory Animal Resources, and ▽Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Ellis
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
authors.forename: Alan
authors.initials: A
authors.lastname: Bass
authors.forename: John W
authors.initials: JW
authors.lastname: Butcher
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Byford
authors.forename: Anthony
authors.initials: A
authors.lastname: Donofrio
authors.forename: Sheila
authors.initials: S
authors.lastname: Galloway
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Haidle
authors.forename: James
authors.initials: J
authors.lastname: Jewell
authors.forename: Nancy
authors.initials: N
authors.lastname: Kelly
authors.forename: Erica K
authors.initials: EK
authors.lastname: Leccese
authors.forename: Sandra
authors.initials: S
authors.lastname: Lee
authors.forename: Matthew
authors.initials: M
authors.lastname: Maddess
authors.forename: J Richard
authors.initials: JR
authors.lastname: Miller
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.forename: Ekundayo
authors.initials: E
authors.lastname: Osimboni
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Otte
authors.forename: M Vijay
authors.initials: MV
authors.lastname: Reddy
authors.forename: Kerrie
authors.initials: K
authors.lastname: Spencer
authors.forename: Binyuan
authors.initials: B
authors.lastname: Sun
authors.forename: Stella H
authors.initials: SH
authors.lastname: Vincent
authors.forename: Gwendolyn J
authors.initials: GJ
authors.lastname: Ward
authors.forename: Grace H C
authors.initials: GH
authors.lastname: Woo
authors.forename: Chiming
authors.initials: C
authors.lastname: Yang
authors.forename: Hani
authors.initials: H
authors.lastname: Houshyar
authors.forename: Alan B
authors.initials: AB
authors.lastname: Northrup
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009152:Mutagenicity Tests; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D051638:Ether-A-Go-Go Potassium Channels; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases