Escape from adamantane: Scaffold optimization of novel P2X7 antagonists featuring complex polycycles

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Barniol-Xicota, Marta^1,2  Kwak, Seung-Hwa³  Lee, So-Deok³  Caseley, Emily⁴  Valverde, Elena^1,2  Jiang, Lin-Hua⁴  Kim, Yong-Chul³  Vazquez, Santiago^1,2 

[1] Univ Barcelona, Fac Farm & Ciencies Alimentacio, Lab Quim Farmaceut, Unitat Associada CSIC, Ave Joan 23 27-31, E-08028 Barcelona, Spain

[2] Univ Barcelona, Inst Biomed IBUB, Ave Joan 23 27-31, E-08028 Barcelona, Spain

[3] Gwangju Inst Sci & Technol GIST, Sch Life Sci, Gwangju 500712, South Korea

[4] Univ Leeds, Sch Biomed Sci, Leeds, W Yorkshire, England

关键词: Adamantane;    Drug discovery;    Homology models;    P2X7 antagonists;    Scaffold replacement;   

DOI  :  10.1016/j.bmcl.2017.01.039

来源: Elsevier

【 摘 要 】

The adamantane scaffold, despite being widely used in medicinal chemistry, is not devoid of problems. In recent years we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As an adamantane scaffold is a common structural feature in several P2X7 receptor antagonists, herein we report the synthesis and pharmacological evaluation of multiple replacement options of adamantane that maintain a good activity profile. Molecular modeling studies support the binding of the compounds to a site close to the central pore, rather than to the ATP-binding site and shed light on the structural requirements for novel P2X7 antagonists. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free