2. Academic Validation
  3. Escape from adamantane: Scaffold optimization of novel P2X7 antagonists featuring complex polycycles

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

  • Bioorg Med Chem Lett. 2017 Feb 15;27(4):759-763. doi: 10.1016/j.bmcl.2017.01.039.
Marta Barniol-Xicota 1,  Seung-Hwa Kwak 2,  So-Deok Lee 2,  Emily Caseley 3,  Elena Valverde 1,  Lin-Hua Jiang 3,  Yong-Chul Kim 4,  Santiago Vázquez 5
Affiliations

Affiliations

  • 1 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, Barcelona E-08028, Spain.
  • 2 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
  • 3 School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom.
  • 4 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea. Electronic address: yongchul@gist.ac.kr.
  • 5 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, Barcelona E-08028, Spain. Electronic address: svazquez@ub.edu.
PMID: 28126517 DOI: 10.1016/j.bmcl.2017.01.039
Abstract

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.

Keywords

Adamantane; Drug discovery; Homology models; P2X7 antagonists; Scaffold replacement.

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