title: Design, synthesis and evaluation of novel 5-phenylpyridin-2(1H)-one derivatives as potent reversible Bruton's tyrosine kinase inhibitors.
abstract: A series of novel reversible Btk inhibitors has been designed based on the structure of the recently reported preclinical drug RN486. The synthesis and SAR of these compounds are described. Among these derivatives, compound 16b was identified to be a potent and orally available reversible agent with satisfactory Btk enzymatic and cellular inhibition in vitro, as well as favorable PK properties and inhibition of arthritis in vivo.
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: 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: Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Yanliang
authors.initials: Y
authors.lastname: Ren
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: Feng
authors.initials: F
authors.lastname: Tang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Jiang
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: 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: Jie
authors.initials: J
authors.lastname: Yang
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: Shifu
authors.initials: S
authors.lastname: Mo
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: D000284:Administration, Oral; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D005260:Female; D006207:Half-Life; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: C000601003:6-cyclopropyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)isoquinolin-1(2H)-one; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C000588993:RN486; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
keywords: Efficacy; In vivo; Reversible Btk inhibitors; SAR; Structure