Referenced in: none

Automatically associated channels: Kv11.1

Title: Overcoming mutagenicity and ion channel activity: optimization of selective spleen tyrosine kinase inhibitors.

Authors: J Michael Ellis, Michael D Altman, Alan Bass, John W Butcher, Alan J Byford, Anthony Donofrio, Sheila Galloway, Andrew M Haidle, James Jewell, Nancy Kelly, Erica K Leccese, Sandra Lee, Matthew 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

Journal, date & volume: J. Med. Chem., 2015 Feb 26 , 58, 1929-39

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25625541

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.