| Texto completo | |
| Autor(es): |
Abdalrahman, Rayan Aboalgasim Makawi
;
Schlegel, Katja
;
Fernandes, Victor Hugo Catricala
;
Dotz, Adeline
;
Clososki, Giuliano Cesar
;
Junker, Anna
Número total de Autores: 6
|
| Tipo de documento: | Artigo Científico |
| Fonte: | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 302, p. 30-pg., 2026-01-15. |
| Resumo | |
The P2Y2 receptor is a G protein-coupled receptor activated by extracellular nucleotides, is implicated in various pathologies, including cancer and inflammatory diseases. Despite its therapeutic relevance, potent and selective P2Y2R antagonists remain limited. Here, we report a comprehensive structure-activity relationship (SAR) study based on the clinical tool compound AR-C118925, aiming to enhance P2Y2R selectivity and drug-like properties through bioisosteric replacement of the tetrazole moiety via late-stage diversification. A diverse library of over 60 derivatives was synthesized and evaluated in Ca2+-flux assays. Multiple bioisosteres, including isoquinolinone and quinolinone scaffolds, retained or improved P2Y2R antagonistic potency while mitigating off-target activity, especially at P2X receptors. The most potent compound, 32g, demonstrated nanomolar potency (pIC50 = 7.78 +/- 0.13) and high selectivity over other P2X subtypes. Structure-based modeling provided insights into ligand-receptor interactions guiding antagonistic potency. Collectively, these results provide a valuable scaffold for the development of selective and orally bioavailable P2Y2R antagonists. (AU) | |
| Processo FAPESP: | 22/05327-7 - Explorando o espaço químico medicinal de aromáticos com ferramentas sintéticas altamente seletivas |
| Beneficiário: | Giuliano Cesar Clososki |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 23/16292-2 - Desenvolvimento de um inibidor alostérico de cd73 e marcador para pet. |
| Beneficiário: | Victor Hugo Catricala Fernandes |
| Modalidade de apoio: | Bolsas no Exterior - Estágio de Pesquisa - Doutorado |