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Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties.
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- Additional Information
- Source:
Publisher: American Chemical Society Country of Publication: United States NLM ID: 101197791 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1543-8392 (Electronic) Linking ISSN: 15438384 NLM ISO Abbreviation: Mol Pharm Subsets: MEDLINE
- Publication Information:
Original Publication: Washington, DC : American Chemical Society, c2004-
- Subject Terms:
Anti-Inflammatory Agents/
*pharmacology ;
Inflammation Mediators/
*metabolism ;
Receptors, Prostaglandin E, EP2 Subtype/
*antagonists & inhibitors ;
Up-Regulation/
*drug effects;
Animals ;
Anti-Inflammatory Agents/
chemistry ;
Anti-Inflammatory Agents/
therapeutic use ;
Arthritis, Rheumatoid/
drug therapy ;
Arthritis, Rheumatoid/
immunology ;
Cell Line ;
Dinoprostone/
immunology ;
Dinoprostone/
metabolism ;
Drug Evaluation, Preclinical ;
Endometriosis/
drug therapy ;
Endometriosis/
immunology ;
Female ;
Half-Life ;
Inflammation Mediators/
immunology ;
Male ;
Mice ;
Mice, Inbred C57BL ;
Neoplasms/
drug therapy ;
Neoplasms/
immunology ;
Rats ;
Receptors, Prostaglandin/
metabolism ;
Receptors, Prostaglandin E, EP2 Subtype/
immunology ;
Receptors, Prostaglandin E, EP2 Subtype/
metabolism ;
Receptors, Prostaglandin E, EP4 Subtype/
metabolism ;
Solubility ;
Up-Regulation/
immunology ;
Water/
chemistry - Abstract:
The prostaglandin E 2 receptor, EP2, plays an important role in physiology and in a variety of pathological conditions. Studies indicate that EP2 is pro-inflammatory in chronic peripheral and central nervous system disease and cancer models. Thus, targeting the EP2 receptor with small molecules could be a therapeutic strategy for treating inflammatory diseases and cancer. We recently reported a novel class of competitive antagonists of the EP2 receptor. However, earlier leads displayed low selectivity against the DP1 prostanoid receptor, moderate plasma half-life, and low aqueous solubility, which renders them suboptimal for testing in animal models of disease. We now report a novel compound TG8-69, which has suitable drug-like properties. We present synthesis, lead-optimization studies, pharmacological characterization, and anti-inflammatory properties of this compound that support its use in chronic peripheral inflammatory diseases, including rheumatoid arthritis, endometriosis, and cancer, in which EP2 appears to play a pathogenic role.
- References:
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- Grant Information:
R01 NS097776 United States NS NINDS NIH HHS; R21 NS101167 United States NS NINDS NIH HHS; R33 NS101167 United States NS NINDS NIH HHS; U01 AG052460 United States AG NIA NIH HHS
- Contributed Indexing:
Keywords: EP2 antagonist; anti-inflammatory; aqueous-solubility; cytokines; lead-optimization; tetrazole
- Accession Number:
0 (Anti-Inflammatory Agents)
0 (Inflammation Mediators)
0 (PTGER2 protein, human)
0 (Receptors, Prostaglandin)
0 (Receptors, Prostaglandin E, EP2 Subtype)
0 (Receptors, Prostaglandin E, EP4 Subtype)
0 (prostanoid D receptor 1, human)
059QF0KO0R (Water)
K7Q1JQR04M (Dinoprostone)
- Publication Date:
Date Created: 20181107 Date Completed: 20190909 Latest Revision: 20220409
- Publication Date:
20240829
- Accession Number:
PMC6633905
- Accession Number:
10.1021/acs.molpharmaceut.8b00764
- Accession Number:
30398879
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