Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability. Issue 2 (15th January 2016)

• Record Type: Journal Article
• Authors: Young, Wendy B.; Barbosa, James; Blomgren, Peter; Bremer, Meire C.; Crawford, James J.; Dambach, Donna; Eigenbrot, Charles; Gallion, Steve; Johnson, Adam R.; Kropf, Jeffrey E.; Lee, Seung H.; Liu, Lichuan; Lubach, Joseph W.; Macaluso, Jen; Maciejewski, Pat; Mitchell, Scott A.; Ortwine, Daniel F.; Di Paolo, Julie; Reif, Karin; Scheerens, Heleen; Schmitt, Aaron; Wang, Xiaojing; Wong, Harvey; Xiong, Jin-Ming; Xu, Jianjun; Yu, Christine; Zhao, Zhongdong; Currie, Kevin S.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 2(2016)
• Page Start: 575
• Page End: 579
• Publication Date: 2016-01-15
• Subjects: Kinase inhibitor -- Bruton's tyrosine kinase (BTK) -- Rheumatoid arthritis -- Pyridazinone; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.11.076
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 analog23, possessing improved potency, metabolic stability and preclinical properties.