Literature DB >> 24974342

The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists.

David W Porter1, Michelle Bradley2, Zarin Brown2, Steven J Charlton2, Brian Cox2, Peter Hunt2, Diana Janus2, Sarah Lewis2, Paul Oakley2, Des O'Connor2, John Reilly2, Nichola Smith2, Neil J Press2.   

Abstract

A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrimidine 2-((2,6-dichlorobenzyl)thio)-5-isocyano-6-phenylpyrimidin-4-ol 4, resulting in the discovery of CXCR2 receptor antagonist 2-((2,3-difluorobenzyl)thio)-6-(2-(hydroxymethyl)cyclopropyl)-5-isocyanopyrimidin-4-ol 24. The SAR was investigated by systematic variation of the aromatic group at c-6, the linker between c-2 and the halogenated ring, and the c-5 nitrile moiety.
Copyright © 2014 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  COPD; CXCR2; Chemokines; Neutrophils; Pyrimidine

Mesh：

Substances：

Year:  2014        PMID： 24974342     DOI： 10.1016/j.bmcl.2014.06.011

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  6 in total

1.  Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model.

Authors:  Dean Y Maeda; Angela M Peck; Aaron D Schuler; Mark T Quinn; Liliya N Kirpotina; Winston N Wicomb; Richard L Auten; Rambabu Gundla; John A Zebala
Journal:  Bioorg Med Chem Lett       Date:  2015-04-23       Impact factor: 2.823

2.  Discovery of CNS Penetrant CXCR2 Antagonists for the Potential Treatment of CNS Demyelinating Disorders.

Authors:  Heng Xu; Hongfu Lu; Zhongmiao Xu; Linbo Luan; Chengyong Li; Yan Xu; Kelly Dong; Jinqiang Zhang; Xiong Li; Yvonne Li; Gentao Liu; Sophie Gong; Yong-Gang Zhao; Ailian Liu; Yueting Zhang; Wei Zhang; Xin Cai; Jia-Ning Xiang; John D Elliott; Xichen Lin
Journal:  ACS Med Chem Lett       Date:  2016-02-08       Impact factor: 4.345

3.  Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability.

Authors:  Aaron D Schuler; Courtney A Engles; Dean Y Maeda; Mark T Quinn; Liliya N Kirpotina; Winston N Wicomb; S Nicholas Mason; Richard L Auten; John A Zebala
Journal:  Bioorg Med Chem Lett       Date:  2015-07-30       Impact factor: 2.823

Review 4.  Transcriptional regulation of chemokine genes: a link to pancreatic islet inflammation?

Authors:  Susan J Burke; J Jason Collier
Journal:  Biomolecules       Date:  2015-05-26

Review 5.  Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases.

Authors:  Helen Ha; Bikash Debnath; Nouri Neamati
Journal:  Theranostics       Date:  2017-04-07       Impact factor: 11.556

6.  Three successive and regiocontroled palladium cross-coupling reactions to easily synthesize novel series of 2,4,6-tris(het)aryl pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines.

Authors:  R Belaroussi; A Ejjoummany; A El Hakmaoui; M Akssira; G Guillaumet; S Routier
Journal:  RSC Adv       Date:  2018-01-02       Impact factor: 3.361
  6 in total

北京卡尤迪生物科技股份有限公司 © 2022-2023.