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J Med Chem ; 65(22): 15066-15084, 2022 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-36346645

RESUMEN

Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a brain-relevant kinase and an emerging drug target for ischemic stroke and neurodegenerative disorders. Despite reported CaMKIIα inhibitors, their usefulness is limited by low subtype selectivity and brain permeability. (E)-2-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (NCS-382) is structurally related to the proposed neuromodulator, γ-hydroxybutyric acid, and is a brain-penetrating high nanomolar-affinity ligand selective for the CaMKIIα hub domain. Herein, we report the first series of NCS-382 analogs displaying improved affinity and preserved brain permeability. Specifically, we present Ph-HTBA (1i) with enhanced mid-nanomolar affinity for the CaMKIIα binding site and a marked hub thermal stabilization effect along with a distinct CaMKIIα Trp403 flip upon binding. Moreover, Ph-HTBA has good cellular permeability and low microsomal clearance and shows brain permeability after systemic administration to mice, signified by a high Kp, uu value (0.85). Altogether, our study highlights Ph-HTBA as a promising candidate for CaMKIIα-associated pharmacological interventions and future clinical development.


Asunto(s)
Benzocicloheptenos , Encéfalo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Animales , Ratones , Benzocicloheptenos/farmacología , Sitios de Unión , Encéfalo/metabolismo , Unión Proteica , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores
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