1. Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability.
- Author
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Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, Eigenbrot C, Gallion S, Johnson AR, Kropf JE, Lee SH, Liu L, Lubach JW, Macaluso J, Maciejewski P, Mitchell SA, Ortwine DF, Di Paolo J, Reif K, Scheerens H, Schmitt A, Wang X, Wong H, Xiong JM, Xu J, Yu C, Zhao Z, and Currie KS
- Subjects
- Agammaglobulinaemia Tyrosine Kinase, Animals, Dogs, Humans, Mice, Microsomes, Liver metabolism, Models, Molecular, Protein Kinase Inhibitors metabolism, Protein Kinase Inhibitors pharmacokinetics, Protein-Tyrosine Kinases metabolism, Pyridazines metabolism, Pyridazines pharmacokinetics, Pyrimidinones metabolism, Pyrimidinones pharmacokinetics, Rats, Thiophenes metabolism, Thiophenes pharmacokinetics, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Pyridazines chemistry, Pyridazines pharmacology, Pyrimidinones chemistry, Pyrimidinones pharmacology, Thiophenes chemistry, Thiophenes pharmacology
- Abstract
BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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