title: Discovery of novel Bruton's tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2,3-d]pyrimidine scaffold.
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=4.8nM) and cellular inhibition (IC50=17nM) assays to that of RN486.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Xinge
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, No 152, Luoyu Road, Wuhan 430079, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No 76, Yanta West Road, Xi'an 710061, PR China.
authors.forename: Minhang
authors.initials: M
authors.lastname: Xin
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Cai
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Tang
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China. Electronic address: xianghua@cpu.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Xiang
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C030986:pyrimidine
keywords: BTK inhibitors; Pyrrolo[23-d]pyrimidine; SAR