Carbamate JNK3 Inhibitors Show Promise as Effective Treatments for Alzheimer’s Disease: In Vivo Studies on Mouse Models

We have been developing new inhibitors for c-Jun N-terminal
kinase
3 (JNK3) as a potential treatment for Alzheimer’s disease (AD).
We identified potential JNK3 inhibitors through pharmacodynamic optimization
studies, including benzimidazole compounds 2 and 3, but their unreliable pharmacokinetic properties led us
to develop carbamate inhibitors 2h and 3h. In vitro studies validated carbamate inhibitors 2h and 3h as potent and highly selective JNK3 inhibitors
with favorable pharmacokinetic profiles. Oral administration of 2h and 3h to both APP/PS1 and 3xTg AD mouse models
improved cognitive function, indicating their potential as effective
treatments for Alzheimer’s disease. Carbamate JNK3 inhibitor 3h, in particular, restored cognitive function to near-normal
levels in the 3xTg mice model of AD and led to pTau reduction in the
hippocampal tissues of 3xTg-AD mice during in vivo behavioral evaluations. We intend to further develop these carbamate
JNK3 inhibitors in preclinical studies as a potential first-in-class
treatment for AD.