Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD mouse model

• Published in: Bioorganic & medicinal chemistry letters Vol. 80; pp. 129108 - 129114
• Main 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.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.01.2023; Elsevier
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Animals; B cell; B7-2 Antigen; BTK; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Disease Models, Animal; Fsp3; Life Sciences & Biomedicine; Mice; Non-covalent inhibitor; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - chemistry; Protein-Tyrosine Kinases; Science & Technology; Selectivity; X-ray; BTK; Fsp3; B cell; Selectivity; X-ray; Non-covalent inhibitor; BRUTONS TYROSINE KINASE; DESIGN; IBRUTINIB; Fsp
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2022.129108

[Display omitted] 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.