Design, synthesis and evaluation of pyrrolo[2,3-d]pyrimidine-phenylamide hybrids as potent Janus kinase 2 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 12; pp. 2936 - 2941
• Main Authors: Wang, Tingfang, Liu, Xiaofei, Hao, Meixi, Qiao, Jianan, Ju, Caoyun, Xue, Lingjing, Zhang, Can
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-06-2016
• Subjects: Amides - administration & dosage; Amides - chemistry; Amides - pharmacology; Animals; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Design; Humans; Hybridization; JAK2 inhibitors; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; Mice; Molecular Docking Simulation; Molecular Structure; Myeloproliferative neoplasms; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - administration & dosage; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrroles - administration & dosage; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrrolo[2,3-d]pyrimidine; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; JAK2 inhibitors; Hybridization; Pyrrolo[2,3-d]pyrimidine; Myeloproliferative neoplasms
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.04.027

A series of novel pyrrolo[2,3-d]pyrimidine-phenylamide hybrids were designed using the hybridization strategy and synthesized as potential JAK2 inhibitors. [Display omitted]
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).