title: Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.
abstract: 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 TA97aSalmonellastrain.
authors.affiliation: Department of Discovery Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Ellis
authors.affiliation: Department of Discovery Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
authors.affiliation: Department of Discovery Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Brandon
authors.initials: B
authors.lastname: Cash
authors.affiliation: Department of Discovery Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Haidle
authors.affiliation: Department of Discovery Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Kubiak
authors.affiliation: Department of Discovery Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Maddess
authors.affiliation: Department of Discovery Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Discovery Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Northrup
keywords: Spleen tyrosine kinase; intramolecular hydrogen bond; structure-based drug design