2-Aminopyrimidin-4(1H)-one as the novel bioisostere of urea: discovery of novel and potent CXCR2 antagonists

Hongfu Lu; Ting Yang; Zhongmiao Xu; Paul B Wren; Yueting Zhang; Xin Cai; Metul Patel; Kelly Dong; Qing Zhang; Wei Zhang; Xiaoming Guan; Jianing Xiang; John D Elliott; Xichen Lin; Feng Ren

doi:10.1016/j.bmcl.2014.10.003

2-Aminopyrimidin-4(1H)-one as the novel bioisostere of urea: discovery of novel and potent CXCR2 antagonists

Bioorg Med Chem Lett. 2014 Dec 1;24(23):5493-6. doi: 10.1016/j.bmcl.2014.10.003. Epub 2014 Oct 12.

Authors

Affiliations

¹ Research and Development, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China.
² GlaxoSmithKline, Platform Technology & Science, Biological Sciences, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK.
³ Research and Development, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China. Electronic address: [email protected].

PMID: 25455491
DOI: 10.1016/j.bmcl.2014.10.003

Abstract

2-Aminopyrimidin-4(1H)-one was proposed as the novel bioisostere of urea. Bioisosteric replacement of the reported urea series of the CXCR2 antagonists with 2-aminopyrimidin-4(1H)-ones led to the discovery of the novel and potent CXCR2 antagonist 3e. 2-Aminopyrimidin-4(1H)-one derivative 3e demonstrated a good developability profile (reasonable solubility and high permeability) and superior chemical stability especially in simulated gastric fluid (SGF) compared with ureas.

Keywords: 2-Aminopyrimidin-4(1H)-one; Bioisostere; CXCR2 antagonists; Urea.

MeSH terms

Humans
Molecular Structure
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology
Receptors, Interleukin-8B / antagonists & inhibitors*
Structure-Activity Relationship
Urea / analogs & derivatives*

Substances

Pyrimidines
Receptors, Interleukin-8B
Urea