Amaradhi, Radhika; Mohammed, Shabber; Banik, Avijit; Franklin, Ronald; Dingledine, Raymond; Ganesh, Thota published the artcile< Second-Generation Prostaglandin Receptor EP2 Antagonist, TG8-260, with High Potency, Selectivity, Oral Bioavailability, and Anti-Inflammatory Properties>, Formula: C9H7BrO3, the main research area is inflammation antiinflammatory lead optimization pharmacokinetics CYP450 inhibition competitive antagonism.
EP2, a G-protein-coupled prostaglandin-E2 receptor, has emerged as a seminal biol. target for drug discovery. EP2 receptor activation is typically proinflammatory; therefore, the development of EP2 antagonists to mitigate the severity and disease pathol. in a variety of inflammation-driven central nervous system and peripheral disorders would be a novel strategy. We have recently developed a second-generation EP2 antagonist TG8-260 and shown that it reduces hippocampal neuroinflammation and gliosis after pilocarpine-induced status epilepticus in rats. Here, we present details of synthesis, lead optimization on earlier leads that resulted in TG8-260 (I), potency and selectivity evaluations using cAMP-driven time-resolved fluorescence resonance energy-transfer (TR-FRET) assays and [H3]-PGE2-binding assays, absorption, distribution, metabolism, and excretion (ADME), and pharmacokinetics. TG8-260 (2f) showed Schild KB = 13.2 nM (3.6-fold more potent than the previous lead TG8-69 (1c)) and 500-fold selectivity to EP2 against other prostanoid receptors. Pharmacokinetic data indicated that TG8-260 has a plasma half-life of 2.14 h (PO) and excellent oral bioavailability (77.3%). Extensive ADME tests indicated that TG8-260 is a potent inhibitor of CYP450 enzymes. Further, we show that TG8-260 displays antagonistic activity on the induction of EP2 receptor-mediated inflammatory gene expression in microglia BV2-hEP2 cells; therefore, it can serve as a tool for investigating anti-inflammatory pathways in peripheral inflammatory disease animal models.
ACS Pharmacology & Translational Science published new progress about 5-HT2A receptors Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 20099-90-5 belongs to class bromides-buliding-blocks, and the molecular formula is C9H7BrO3, Formula: C9H7BrO3.
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary