Carbamate JNK3 Inhibitors Show Promise as Effective Treatments for Alzheimer’s Disease: In Vivo Studies on Mouse Models
Joonhong Jun, Hyungwoo Moon, Songyi Yang, Jung-Hun Lee, Jihyun Baek, Hyejin Kim, Hyunwook Cho, Kyungrim Hwang, Soyeon Ahn, Yuro Kim, Gibeom Kim, HyunTae Kim, Ho‐Seok Kwon, Jung‐Mi Hah
Abstract
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.