Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD mouse model. (15th January 2023)

• Record Type: Journal Article
• Authors: Vandeveer, George H.; Arduini, Robert M.; Baker, Darren P.; Barry, Kevin; Bohnert, Tonika; Bowden-Verhoek, Jon K.; Conlon, Patrick; Cullen, Patrick F.; Guan, Bing; Jenkins, Tracy J.; Liao, Shu-Yu; Lin, Lin; Liu, Yu-Ting; Marcotte, Douglas; Mertsching, Elisabeth; Metrick, Claire M.; Negrou, Ella; Powell, Noel; Scott, Daniel; Silvian, Laura F.; Hopkins, Brian T.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 80(2023)
• Publication Date: 2023-01-15
• Subjects: BTK -- Non-covalent inhibitor -- Fsp3 -- Selectivity -- X-ray -- B cell; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.129108
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: For the past two decades, BTK a tyrosine kinase and member of the Tec family has been a drug target of significant interest due to its potential to selectively treat various B cell-mediated diseases such as CLL, MCL, RA, and MS. Owning to the challenges encountered in identifying drug candidates exhibiting the potency block B cell activation via BTK inhibition, the pharmaceutical industry has relied on the use of covalent/irreversible inhibitors to address this unmet medical need. Herein, we describe a medicinal chemistry campaign to identify structurally diverse reversible BTK inhibitors originating from HITS identified using a fragment base screen. The leads were optimized to improve the potency and in vivo ADME properties resulting in a structurally distinct chemical series used to develop and validate a novel in vivo CD69 and CD86 PD assay in rodents.