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Bioorg Med Chem Lett. 2014 Aug 15;24(16):4044-7. doi: 10.1016/j.bmcl.2014.05.072. Epub 2014 Jun 2.

2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists.

Author information

1
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
2
National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
3
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
4
Grunenthal Innovation, Grunenthal GmbH, D-52078 Aachen, Germany.
5
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: jeewoo@snu.ac.kr.

Abstract

A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode.

KEYWORDS:

Capsaicin; Molecular modeling; Resiniferatoxin; TRPV1 antagonist; Vanilloid receptor 1

PMID:
25011915
PMCID:
PMC6980356
DOI:
10.1016/j.bmcl.2014.05.072
[Indexed for MEDLINE]
Free PMC Article

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