Discovery of novel Bruton's tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2,3-d]pyrimidine scaffold

Xinge Zhao; Wei Huang; Yazhou Wang; Minhang Xin; Qiu Jin; Jianfeng Cai; Feng Tang; Yong Zhao; Hua Xiang

doi:10.1016/j.bmc.2014.10.043

Discovery of novel Bruton's tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2,3-d]pyrimidine scaffold

Bioorg Med Chem. 2015 Feb 15;23(4):891-901. doi: 10.1016/j.bmc.2014.10.043. Epub 2014 Nov 6.

Authors

Xinge Zhao¹, Wei Huang², Yazhou Wang³, Minhang Xin⁴, Qiu Jin³, Jianfeng Cai³, Feng Tang³, Yong Zhao³, Hua Xiang⁵

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

PMID: 25596757
DOI: 10.1016/j.bmc.2014.10.043

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.

Keywords: BTK inhibitors; Pyrrolo[23-d]pyrimidine; SAR.

Publication types

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

MeSH terms

Agammaglobulinaemia Tyrosine Kinase
Humans
Molecular Docking Simulation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Pyrimidines / chemistry*
Pyrimidines / pharmacology*
Pyrroles / chemistry
Pyrroles / pharmacology
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human
pyrimidine