Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors. Issue 2 (15th January 2016)

• Record Type: Journal Article
• Authors: Achary, Raghavendra; Yun, Jeong In; Park, Chi Min; Mathi, Gangadhar Rao; Lee, Joo Yun; Ha, Jae Du; Chae, Chong Hak; Ahn, Sunjoo; Park, Chi Hoon; Lee, Chong Ock; Hwang, Jong Yeon; Yun, Chang-Soo; Jung, Hee Jung; Cho, Sung Yun; Kim, Hyoung Rae; Kim, Pilho
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 2(2016)
• Page Start: 207
• Page End: 219
• Publication Date: 2016-01-15
• Subjects: ALK -- Cancer -- NSCLC -- LDK378 -- Tetrahydroisoquinoline (THIQ); 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.2015.12.004
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of8 and17 as highly potent ALK inhibitors. THIQs8 and17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a –o and17a –i ) prepared were not as active as their parent compounds, both8 and17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378.