title: Design, synthesis and evaluation of pyrrolo[2,3-d]pyrimidine-phenylamide hybrids as potent Janus kinase 2 inhibitors.
abstract: Janus kinase 2 (JAK2) plays an essential role in the signaling of hormone-like cytokines and growth factors, which has been convinced as an important target of myeloproliferative neoplasms (MPNs) therapy. In this study, a series of novel pyrrolo[2,3-d]pyrimidine-phenylamide hybrids were designed and synthesized as potential JAK2 inhibitors through hybridization strategy. In vitro biological studies showed that most of these compounds exhibited potent activity against JAK2. Especially, compound 16c was identified as a suitable lead compound, which showed favorable pharmacokinetic profiles in rats (F=73.57%), excellent in vitro efficacy against erythroleukemic cells (TF-1, IC50=0.14μM), and high selectivity for JAK2 (IC50=6nM with >97-fold selectivity vs JAK3).
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Tingfang
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Meixi
authors.initials: M
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Jianan
authors.initials: J
authors.lastname: Qiao
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Caoyun
authors.initials: C
authors.lastname: Ju
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: xuelingjing65@163.com.
authors.forename: Lingjing
authors.initials: L
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: zhangcan@cpu.edu.cn.
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C450639:Pyrrolo(2,3-d)pyrimidine; D053614:Janus Kinase 2
keywords: Hybridization; JAK2 inhibitors; Myeloproliferative neoplasms; Pyrrolo[2,3-d]pyrimidine