Discovery of novel BTK inhibitors with carboxylic acids

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 6; pp. 1471 - 1477
• Main Authors: Gao, Xiaolei, Wang, James, Liu, Jian, Guiadeen, Deodial, Krikorian, Arto, Boga, Sobhana Babu, Alhassan, Abdul-Basit, Selyutin, Oleg, Yu, Wensheng, Yu, Younong, Anand, Rajan, Liu, Shilan, Yang, Chundao, Wu, Hao, Cai, Jiaqiang, Cooper, Alan, Zhu, Hugh, Maloney, Kevin, Gao, Ying-Duo, Fischmann, Thierry O., Presland, Jeremy, Mansueto, My, Xu, Zangwei, Leccese, Erica, Zhang-Hoover, Jie, Knemeyer, Ian, Garlisi, Charles G., Bays, Nathan, Stivers, Peter, Brandish, Philip E., Hicks, Alexandra, Kim, Ronald, Kozlowski, Joeseph A.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.03.2017; Elsevier
• Subjects: Adenosine uptake activity; Animals; BTK inhibitor; Carboxylic acid ribose pocket; Carboxylic Acids - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Discovery; hPBMC and hWB; Humans; Life Sciences & Biomedicine; Off target selectivities; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Rats; Science & Technology; Carboxylic acid ribose pocket; Adenosine uptake activity; BTK inhibitor; Off target selectivities; hPBMC and hWB; RHEUMATOID-ARTHRITIS; BRUTONS TYROSINE KINASE; DISEASES; B-CELL MALIGNANCIES
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.11.079

[Display omitted] We report the design and synthesis of a series of novel Bruton’s Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.