期刊
MOLECULAR PHARMACEUTICS
卷 15, 期 12, 页码 5809-5817出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.8b00764
关键词
EP2 antagonist; aqueous-solubility; cytokines; tetrazole; lead-optimization; anti-inflammatory
资金
- NIH/NIA [U01 AG052460]
- ADDF grant [20131001, R01 NS097776, R21 NS101167]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS101167, R01NS097776] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [U01AG052460] Funding Source: NIH RePORTER
The prostaglandin E2 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.
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