Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization

被引：6

作者：

Ellis, J. Michael ^{[1
]}

Altman, Michael D. ^{[1
]}

Cash, Brandon ^{[1
]}

Haidle, Andrew M. ^{[1
]}

Kubiak, Rachel L. ^{[1
]}

Maddess, Matthew L. ^{[1
]}

Yan, Youwei ^{[1
]}

Northrup, Alan B. ^{[1
]}

机构：

[1] Merck & Co Inc, Dept Discovery Chem, 33 Ave Louis Pasteur, Boston, MA 02115 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 12期

关键词：

Spleen tyrosine kinase; intramolecular hydrogen bond; structure-based drug design; FOSTAMATINIB DISODIUM; DISCOVERY; INFLAMMATION; MODELS; POTENT; R788;

D O I：

10.1021/acsmedchemlett.6b00353

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1151 / 1155

页数：5

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