2. Academic Validation
  3. Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2- b]pyridazines as Glycogen Synthase Kinase-3β (GSK-3β) Inhibitors

Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2- b]pyridazines as Glycogen Synthase Kinase-3β (GSK-3β) Inhibitors

  • J Med Chem. 2023 Mar 23;66(6):4231-4252. doi: 10.1021/acs.jmedchem.3c00133.
Richard A Hartz,  Vijay T Ahuja,  Prasanna Sivaprakasam,  Hong Xiao,  Carol M Krause,  Wendy J Clarke,  Kevin Kish,  Hal Lewis,  Nicolas Szapiel,  Ramu Ravirala 1,  Sayali Mutalik 1,  Deepa Nakmode 1,  Devang Shah 1,  Catherine R Burton,  John E Macor,  Gene M Dubowchik
Affiliations

Affiliation

  • 1 Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
PMID: 36950863 DOI: 10.1021/acs.jmedchem.3c00133
Abstract

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 has been implicated in a variety of diseases, including Alzheimer's disease, type 2 diabetes, Cancer, and mood disorders. GSK-3β has been linked to the formation of the neurofibrillary tangles associated with Alzheimer's disease that arise from the hyperphosphorylation of Tau Protein. The design and synthesis of a series of imidazo[1,2-b]pyridazine derivatives that were evaluated as GSK-3β inhibitors are described herein. Structure-activity relationship studies led to the identification of potent GSK-3β inhibitors. In vivo studies with 47 in a triple-transgenic mouse Alzheimer's disease model showed that this compound is a brain-penetrant, orally bioavailable GSK-3β Inhibitor that significantly lowered levels of phosphorylated tau.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z