Neuroinflammation is a key driver of several neurodegenerative diseases including Epilepsy, Parkinson’s diseases, Amyotrophic lateral sclerosis and Alzheimer’ diseases. Prostaglandin-E2 (PGE2) receptor EP2 has emerged as an important target for therapeutic discovery. The EP2 receptor exacerbates the vicious inflammatory signaling during the progression of these central nervous system diseases. EP2 is a Gs-coupled receptor, when activated by the endogenous ligand PGE2, stimulates adenylate cyclase resulting in elevation of cytoplasmic cAMP concentration, which initiates downstream events via protein kinase A (PKA) or exchange protein activated by cAMP (Epac) mediated cell signaling pathways. We developed a cAMP-driven TR-FRET assay in C6-glioma cell line overexpressed with EP2 receptor, and initially screened a small molecule library 262,370 compounds of to identify novel class of antagonists of the EP2 receptor. The first-generation compounds displayed high EP2 potency, but they showed low selectivity against other prostanoid receptors (e.g. DP1 and IP receptors) (Ganesh et al., J. Med. Chem. 2014). Then, we developed second-generation derivatives with high EP2 potency and selectivity, but aqueous solubility and brain permeability properties must be optimized with in the class (Ganesh et al., Eur. J. Med. Chem. 2014). For a chronic oral dosing into animal models of Alzheimer’s disease, we needed a compound with good aqueous solubility and brain permeability properties. Recently, we synthesized &gt; 100 novel derivatives and conducted lead-optimization studies with in the class to identify a novel compound with water solubility and good brain permeability. This novel compound will enable to test proof-of-concept in a variety of animal models of chronic neurodegenerative diseases where EP2 receptor plays deleterious roles. The lead optimization strategies, potency and selectivity (structure activity relationships, SAR), aqueous solubility, ADME and pharmacokinetics data of the novel compounds including the optimized lead compound along with in vitro proof-of-concept that EP2 antagonism is beneficial, will be presented in the meetings.

Development of water soluble, brain permeable EP2 receptor antagonist: Lead-optimization and in vitro proof-of-concept studies

2019 Spring National Meeting

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