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Author Notes:

Phone: +1-404-727-7393. Fax: +1-404-727-0365. E-mail: tganesh@emory.edu

T.G. and R.D. designed the research. T.G., J.J., and M.-S.Y. performed the research. T.G. wrote the manuscript. R.D. helped with the writing.

The authors declare no competing financial interest.

Subjects:

Research Funding:

This work was supported by Alzheimer’s Drug Discovery Foundation (T.G.), NIH/NINDS Grants K99/R00NS082379 (to J.J.) and U01NS058158 (to R.D.), NARSAD Young Investigator Grant (to J.J.), and the Epilepsy Foundation (to J.J.).

National Institutes of Health, United States

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Chemistry, Medicinal
  • Pharmacology & Pharmacy
  • CHEMISTRY, MEDICINAL
  • PROSTAGLANDIN RECEPTOR EP2
  • AMYOTROPHIC-LATERAL-SCLEROSIS
  • COLLAGEN-INDUCED ARTHRITIS
  • TRAUMATIC BRAIN-INJURY
  • ALZHEIMERS-DISEASE
  • PROSTANOID RECEPTORS
  • INFLAMMATORY PROCESSES
  • MICROGLIAL ACTIVATION
  • STATUS EPILEPTICUS
  • OXIDATIVE DAMAGE

Lead Optimization Studies of Cinnamic Amide EP2 Antagonists

Tools:

Journal Title:

Journal of Medicinal Chemistry

Volume:

Volume 57, Number 10

Publisher:

, Pages 4173-4184

Type of Work:

Article | Final Publisher PDF

Abstract:

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 (∼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. © 2014 American Chemical Society.

Copyright information:

© 2014 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

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