Design, synthesis and evaluation of novel 5-phenylpyridin-2(1H)-one derivatives as potent reversible Bruton's tyrosine kinase inhibitors

Xinge Zhao; Minhang Xin; Wei Huang; Yanliang Ren; Qiu Jin; Feng Tang; Hailong Jiang; Yazhou Wang; Jie Yang; Shifu Mo; Hua Xiang

doi:10.1016/j.bmc.2014.11.006

Design, synthesis and evaluation of novel 5-phenylpyridin-2(1H)-one derivatives as potent reversible Bruton's tyrosine kinase inhibitors

Bioorg Med Chem. 2015 Jan 15;23(2):348-64. doi: 10.1016/j.bmc.2014.11.006. Epub 2014 Nov 10.

Authors

Xinge Zhao¹, Minhang Xin², Wei Huang³, Yanliang Ren³, Qiu Jin⁴, Feng Tang⁴, Hailong Jiang⁵, Yazhou Wang⁴, Jie Yang⁴, Shifu Mo⁴, Hua Xiang⁶

Affiliations

¹ 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.
² Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an 710061, PR China.
³ Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
⁴ Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
⁵ Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China.
⁶ Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China. Electronic address: xianghua@cpu.edu.cn.

PMID: 25515957
DOI: 10.1016/j.bmc.2014.11.006

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.

Keywords: Efficacy; In vivo; Reversible Btk inhibitors; SAR; Structure.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Agammaglobulinaemia Tyrosine Kinase
Animals
Arthritis, Rheumatoid / chemically induced
Arthritis, Rheumatoid / drug therapy
Binding Sites
Cell Line
Drug Design*
Female
Half-Life
Humans
Isoquinolines / chemistry
Isoquinolines / pharmacokinetics
Isoquinolines / pharmacology
Male
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Pyridones / chemistry*
Pyridones / pharmacokinetics
Pyridones / pharmacology*
Rats
Rats, Sprague-Dawley
Rats, Wistar
Structure-Activity Relationship

Substances

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
Isoquinolines
Protein Kinase Inhibitors
Pyridones
RN486
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human