Discovery of novel Bruton's tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2, 3-d]pyrimidine scaffold. Issue 4 (15th February 2015)

• Record Type: Journal Article
• Authors: Zhao, Xinge; Huang, Wei; Wang, Yazhou; Xin, Minhang; Jin, Qiu; Cai, Jianfeng; Tang, Feng; Zhao, Yong; Xiang, Hua
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 4(2015)
• Page Start: 891
• Page End: 901
• Publication Date: 2015-02-15
• Subjects: BTK inhibitors -- Pyrrolo[23-d]pyrimidine -- SAR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2014.10.043
• Languages: English
• ISSNs: 0968-0896

Abstract

Abstract : Graphical abstract: Abstract: A series of novel reversible BTK inhibitors was designed based on the structure of the recently reported preclinical drug RN486. Knowledge of the binding mode of RN486 led to the design of new inhibitors that utilized pyrrolo[2, 3- d ]pyrimidine to conformationally restrain key pharmacophoric groups within the molecule. Comprehensive SAR was disclosed and the most promising compound 4x displayed superior activity both in BTK enzyme (IC50 = 4.8 nM) and cellular inhibition (IC50 = 17 nM) assays to that of RN486.