Design and synthesis of tetrahydropyridothieno [2, 3-d] pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain …

…, H Hsu, CH Chen, CY Chang, TY Chang…

Index: Wu, Chia-Hsien; Coumar, Mohane Selvaraj; Chu, Chang-Ying; Lin, Wen-Hsing; Chen, Yi-Rong; Chen, Chiung-Tong; Shiao, Hui-Yi; Rafi, Shaik; Wang, Sing-Yi; Hsu, Hui; Chen, Chun-Hwa; Chang, Chun-Yu; Chang, Teng-Yuan; Lien, Tzu-Wen; Fang, Ming-Yu; Yeh, Kai-Chia; Chen, Ching-Ping; Yeh, Teng-Kuang; Hsieh, Su-Huei; Hsu, John T.-A.; Liao, Chun-Chen; Chao, Yu-Sheng; Hsieh, Hsing-Pang Journal of Medicinal Chemistry, 2010 , vol. 53, # 20 p. 7316 - 7326

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Citation Number: 53

Abstract

HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, ...