Development of second generation EP2 antagonists with high selectivity

• EP2 receptor plays a pro-inflammatory role in CNS and peripheral diseases.
• EP2 deletion is beneficial in models of ALS, Alzheimer's and Parkinson's disease.
• Selective EP2 antagonists are limited so far to use in proof-of-concept studies.
• We developed selective EP2 antagonists and characterized the mechanism of antagonism.

EP2 receptor has emerged as an important biological target for therapeutic intervention. In particular, it has been shown to exacerbate disease progression of a variety of CNS and peripheral diseases. Deletion of the EP2 receptor in mouse models recapitulates several features of the COX-2 inhibition, thus presenting a new avenue for anti-inflammatory therapy which could bypass some of the adverse side effects observed by the COX-2 inhibition therapy. We have recently reported a cinnamic amide class of EP2 antagonists with high potency, but these compounds exhibited a moderate selectivity against prostanoid receptor DP1. Moreover they possess acrylamide moiety in the structure, which may result in liver toxicity over longer period of use in a chronic disease model. Thus, we now developed a second generation compounds that devoid of the acrylamide functionality and possess high potency and improved (>1000-fold) selectivity to EP2 over other prostanoid receptors.

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