一种强效、选择性且口服生物可利用的3,9-二氮杂螺[5.5]十一烷-2-酮CCR5拮抗剂的发现。

Discovery of a potent, selective and orally bioavailable 3,9-diazaspiro[5.5]undeca-2-one CCR5 antagonist.

作者信息

Yang Hanbiao, Lin Xiao-Fa, Padilla Fernando, Gabriel Stephen D, Heilek Gabrielle, Ji Changhua, Sankuratri Surya, deRosier André, Berry Pamela, Rotstein David M

机构信息

Roche Palo Alto LLC, Palo Alto, CA 94304, USA.

出版信息

Bioorg Med Chem Lett. 2009 Jan 1;19(1):209-13. doi: 10.1016/j.bmcl.2008.10.115. Epub 2008 Oct 31.

DOI:10.1016/j.bmcl.2008.10.115

PMID:19014885

Abstract

Replacement of the cyclic carbamate in our previously disclosed 1-oxa-3,9-diazaspiro[5.5]undecan-2-one template led to the discovery of two novel series of 3,9-diazaspiro[5.5]undecane and undeca-2-one CCR5 antagonists. The synthesis, SAR, and antiviral activities of these two series are described. One compound (32) was found to have attractive combination of antiviral potency, selectivity, and pharmacokinetic profile. The asymmetric synthesis of 32 was also accomplished and both enantiomers were equally potent.

摘要

在我们之前公开的1-氧杂-3,9-二氮杂螺[5.5]十一烷-2-酮模板中用环状氨基甲酸酯进行替换，从而发现了两个新型的3,9-二氮杂螺[5.5]十一烷和十一碳-2-酮CCR5拮抗剂系列。描述了这两个系列的合成、构效关系及抗病毒活性。发现一种化合物（32）具有抗病毒效力、选择性和药代动力学特征的诱人组合。还完成了32的不对称合成，且两种对映体的效力相当。