1. Discovery of highly potent and selective Bruton’s tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability
- Author
-
James J. Crawford, Joseph W. Lubach, Peter Blomgren, Pat Maciejewski, Steve Gallion, Jen Macaluso, Julie Di Paolo, Donna Dambach, Adam R. Johnson, Christine Yu, Xiaojing Wang, James Barbosa, Jin-Ming Xiong, Karin Reif, Zhongdong Zhao, Harvey Wong, Aaron C. Schmitt, Kevin S. Currie, Wendy B. Young, Kropf Jeffrey E, Scott A. Mitchell, Heleen Scheerens, Seung H. Lee, Charles Eigenbrot, Meire Bremer, Daniel F. Ortwine, Jianjun Xu, and Lichuan Liu
- Subjects
Models, Molecular ,0301 basic medicine ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pyrimidinones ,Thiophenes ,Cleavage (embryo) ,Biochemistry ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,Amide ,Drug Discovery ,Agammaglobulinaemia Tyrosine Kinase ,Animals ,Humans ,Transferase ,Bruton's tyrosine kinase ,Peptide bond ,Protein Kinase Inhibitors ,Molecular Biology ,biology ,Aryl ,Organic Chemistry ,Metabolism ,Protein-Tyrosine Kinases ,Rats ,Pyridazines ,030104 developmental biology ,chemistry ,Microsomes, Liver ,biology.protein ,Molecular Medicine ,Linker - 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.
- Published
- 2016