486422-54-2

Upstream product

• 57260-71-6 1-t-Butoxycarbonylpiperazine 
• 98-58-8 4-bromobenzenesulfonyl chloride 
• 259808-63-4 4-(4-bromobenzenesulfonyl)piperazine-1-carboxylic acid tert-butyl ester 
• 5419-55-6 Triisopropyl borate 

Relevant academic research and scientific papers

Preparation of targeted GSK3 alpha/beta degradation agent and medical application thereof

The invention discloses preparation of a targeted GSK3 alpha/beta degradation agent and a medical application thereof. The pharmaceutical composition comprises compounds or pharmaceutically acceptable salts thereof as shown in general formulas (I) and (II), R is selected from Cl and I, m is selected from 2, 3, 4, 5 and 6, and n is selected from 1, 2 and 4. The invention provides the degradation agent, and the compound disclosed by the invention can effectively degrade cell GSK3 alpha/beta in a targeting manner, and can be used as a therapeutic agent for Alzheimer's disease or other GSK3 protein related diseases.

Discovery of PT-65 as a highly potent and selective Proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer's disease

GSK3 is a promising target for the treatment of Alzheimer's disease. Here, we describe the design and synthesize of a series of GSK3 degraders based on a click chemistry platform. A series of highly potent GSK3 degraders were obtained. Among them, PT-65 exhibited most potent degradation potency against GSK3α (DC50 = 28.3 nM) and GSK3β (DC50 = 34.2 nM) in SH-SY5Y cells. SPR assay confirmed that PT-65 binds to GSK3β with high affinity (KD = 12.41 nM). The proteomic study indicated that PT-65 could selectively induced GSK3 degradation. Moreover, PT-65 could effectively suppress GSK3β and Aβ mediated tau hyperphosphorylation in a dose-dependent manner and protect SH-SY5Y cells from Aβ caused cell damage. We also confirmed that PT-65 could suppress OA induced tau hyperphosphorylation and ameliorate learning and memory impairments in vivo model of AD. In summary, PT-65 might be a promising candidate for the treatment of AD.

New phenylpyridylpiperazine compounds

A compound selected from those of formula (I): [image] wherein: X represents a C(O) or SO2 group, R1 represents an aryl group or a group NR3R4 wherein R3 and R4 are as defined in the description, R2 represents an alkyl, (C3-C8)cycloalkyl or (C3-C8)cycloalkyl-(C1-C6)alkyl group, its isomers, and addition salts thereof, and medicinal products containing the same which are useful in treating conditions treatable by antagonists of type H3 central histamine receptors.