强效、口服生物可利用的嘧啶-5-甲腈-6-烷基CXCR2受体拮抗剂的发现。
The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists.
作者信息
Porter David W, Bradley Michelle, Brown Zarin, Charlton Steven J, Cox Brian, Hunt Peter, Janus Diana, Lewis Sarah, Oakley Paul, O'Connor Des, Reilly John, Smith Nichola, Press Neil J
机构信息
Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
出版信息
Bioorg Med Chem Lett. 2014 Aug 1;24(15):3285-90. doi: 10.1016/j.bmcl.2014.06.011. Epub 2014 Jun 14.
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.
针对诺华档案筛选命中化合物嘧啶2-((2,6-二氯苄基)硫代)-5-异氰基-6-苯基嘧啶-4-醇4开展了从苗头化合物到先导化合物的优化计划，从而发现了CXCR2受体拮抗剂2-((2,3-二氟苄基)硫代)-6-(2-(羟甲基)环丙基)-5-异氰基嘧啶-4-醇24。通过对C-6位的芳基、C-2位与卤代环之间的连接基团以及C-5位腈基部分进行系统变化来研究构效关系。
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