期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 10, 页码 4173-4184出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm5000672
关键词
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资金
- Alzheimer's Drug Discovery Foundation
- NIH/NINDS [K99/R00NS082379, U01NS058158]
- NARSAD
- Epilepsy Foundation
Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (similar to 10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role.
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