Structure-activity relationship study of thiazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors.

Several human diseases are associated with aberrant epigenetic pathways mediated by histone deacetylases (HDACs), especially HDAC6, a class IIb HDACs, which has emerged as an attractive target for neurodegenerative and autoimmune disease therapeutics. In a previous study, we developed the novel HDAC6-selective inhibitor 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) and showed that it has anti-sepsis activity in vivo. In this study, we conducted structure-activity relationship (SAR) studies to optimize the activity and selectivity of HDAC6, synthesizing its derivatives with various aliphatic linker sizes and cap structures. We identified 6u ((E)-N-hydroxy-3-(2-(4-fluorostyryl)thiazol-4-yl)propanamide), which has nanomolar inhibition activity and a 126-fold selectivity for HDAC6 over HDAC1. Through the docking analyses of 6u against HDAC subtypes, we revealed the importance of the optimal aliphatic linker size, as well as the electronic substituent effect and rigidity of the aryl cap group. Thus, we suggest a new rationale for the design of HDAC6-selective inhibitors.

Compound 9a, a novel synthetic histone deacetylase inhibitor, protects against septic injury in mice by suppressing MAPK signalling.

BACKGROUND AND PURPOSE: Sepsis is a life-threatening clinical condition characterized by uncontrolled inflammatory responses and is a major cause of death in intensive care units. Histone deacetylase (HDAC) inhibitors have recently exhibited anti-inflammatory properties. MAPK phosphatase (MKP) suppresses MAPK signalling, which plays an important role in inflammatory responses. The purpose of this study was to investigate the protective mechanisms of Compound 9a, a newly synthetized HDAC inhibitor, against septic injury. EXPERIMENTAL APPROACH: The anti-inflammatory properties of Compound 9a were assayed in LPS-stimulated RAW264.7 cells. In vivo, polymicrobial sepsis was induced in C57BL/6 mice by caecal ligation and puncture (CLP). The mice were treated with Compound 9a (i.p., 10 mg∙kg(-1) ) 2 h before and immediately after CLP. KEY RESULTS: Compound 9a inhibited the increased production of TNF-α, IL-6 and NO in LPS-stimulated RAW264.7 cells. In mice with CLP, Compound 9a improved survival rate, attenuated organ injuries and decreased serum TNF-α and IL-6 levels. CLP increased expression of toll-like receptor 4, phosphorylated (p)-p38, p-JNK and p-ERK proteins, which was attenuated by Compound 9a. Compound 9a decreased MKP-1 association with HDAC1 and enhanced MKP-1 acetylation and enhanced MKP-1 association with p-p38 and p-ERK. Moreover, the inhibitory effects of Compound 9a on serum cytokine levels and phosphorylation of MAPK were abolished by MKP-1 siRNA. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that Compound 9a protected against septic injury by suppressing MAPK-mediated inflammatory signalling.

Discovery and SAR of N-(1-((substituted piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl)-2-methoxybenzamide derivatives: 5-Hydroxytryptamine receptor 4 agonist as a potent prokinetic agent.

A series of novel benzamide derivatives, altering the 4-fluorophenylalkyl moiety in cisapride, were synthesized as 5-HT4 receptor agonists, and SAR of these analogs was examined on in vitro and in vivo prokinetic activities. These compounds were synthesized for high 5-HT4 receptor binding affinities and low hERG affinities. Several types of analogs were obtained and screened for 5-HT4 binding, hERG blocking, agonism, and gastric emptying assessment. Among the analogues, compound 23g showed promising results compared with the other analogs with respect to gastric emptying rates in rats. Therefore, we suggest that it may be a clinical candidate for the development of a potent prokinetic agent to treat GI disorders.