2. Academic Validation
  3. Design and Synthesis of sEH/HDAC6 Dual-Targeting Inhibitors for the Treatment of Inflammatory Pain

Design and Synthesis of sEH/HDAC6 Dual-Targeting Inhibitors for the Treatment of Inflammatory Pain

  • J Med Chem. 2024 Jul 21. doi: 10.1021/acs.jmedchem.4c00847.
Huashen Xu 1,  Yuanguang Chen 1,  Hua Tong 2,  Lu Chen 1,  Christophe Morisseau 3,  Zijian Zhou 2,  Junning Zhuang 1,  Chuqiao Song 1,  Pengcheng Cai 1,  Zhongbo Liu 4,  Bruce D Hammock 3,  Guoliang Chen 1
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California 95616, United States.
  • 4 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
PMID: 39033411 DOI: 10.1021/acs.jmedchem.4c00847
Abstract

Soluble Epoxide Hydrolase (sEH) and HDAC6 mediate the NF-κB pathway in inflammatory responses, and their inhibitors exhibit powerful anti-inflammatory and analgesic activities in treating both inflammation and pain. Therefore, a series of dual-targeting inhibitors containing urea or squaramide and hydroxamic acid moieties were designed and synthesized, and their role as a new sEH/HDAC6 dual-targeting inhibitor in inflammatory pain was evaluated in a formalin-induced mice model and a xylene-induced mouse ear swelling model. Among them, compounds 28g and 28j showed the best inhibitory and selectivity of sEH and HDAC6. Compound 28g had satisfactory pharmacokinetic characteristics in rats. Following administration at 30 mg/kg, compound 28g exhibited more effective analgesic activity than either an sEH inhibitor (GL-B437) or an HDAC6 Inhibitor (Rocilinostat) alone and coadministration of both inhibitors. Thus, these novel sEH/HDAC6 dual-targeting inhibitors exhibited powerful analgesic activity in nociceptive behavior and are worthy of further development.

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