Open AccessCarboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization
Author(s) -
J. Michael Ellis,
Michael D. Altman,
Brandon Cash,
Andrew M. Haidle,
R.L. Kubiak,
Matthew L. Maddess,
Yong-Bin Yan,
Alan B. Northrup
Publication year - 2016
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.6b00353
Subject(s) - syk , chemistry , moiety , kinome , carboxamide , ames test , ternary complex , protein kinase domain , stereochemistry , tyrosine kinase , kinase , biochemistry , combinatorial chemistry , biology , enzyme , signal transduction , gene , bacteria , salmonella , genetics , mutant
Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a Salmonella strain.