Novel 3-Oxazolidinedione-6-aryl-pyridinones as Potent, Selective, and Orally Active EP₃ Receptor Antagonists

Abstract

High-throughput screening and subsequent optimization led to the discovery of novel 3-oxazolidinedione-6-aryl-pyridinones exemplified by compound 2 as potent and selective EP 3 antagonists with excellent pharmacokinetic properties. Compound 2 was orally active and showed robust in vivo activities in overactive bladder models. To address potential bioactivation liabilities of compound 2, further optimization resulted in compounds 9 and 10, which maintained excellent potency, selectivity, and pharmacokinetic properties and showed no bioactivation liability in glutathione trapping studies. These highly potent, selective, and orally active EP 3 antagonists are excellent tool compounds for investigating and validating potential therapeutic benefits from selectively inhibiting the EP 3 receptor.

Characterization of Biaryl Torsional Energetics and its Treatment in OPLS All-Atom Force Fields

“…3 Arylpyrimidinone substructures have also been featured in some of our FGFR1 kinase inhibitors. 2 Furthermore, 6-aryl-pyridinones have been reported as orally active inhibitors of the EP3 receptor, 30 and as core structures of different non-peptidic inhibitors of human leukocyte elastase 31 and interleukin-1β converting enzyme. 32 Thus, ten 6-aryl-pyridinones were also selected for parameterization ( 21 – 30 in Figure 3).…”

Recent Advances of Pyridinone in Medicinal Chemistry

“…Prostaglandin EP 3 receptor ( Chen and Kuo 2019 ) could regulate the excitability of bladder smooth muscle and is considered a potential target for OAB. Jin et al (2010) reported a series of 3-oxazolidinedione-6-aryl-pyridinones ( 102 ) as selective EP 3 receptor antagonists, generated by the optimization of 100 and 101 which were identified through the high-throughput screening (HTS) method. A thorough investigation on 101 indicated the lead compound exhibited excellent pharmacokinetic profiles and robust potency in several overactive bladder models ( Figure 15 ).…”

“… EP 3 inhibitory activities of 3-oxazolidinedione-6-aryl-pyridinones ( Jin et al, 2010 ). a Value of functional p K i(fp K i) was obtained from a EP 3 fluorometric imaging plate reader (FLIPR) assay.…”

The development of a short route to the API ropinirole hydrochloride

“…Adapting the procedure of Jin et al 34 To a cooled (0 °C) suspension of NaH (310 mg, 7.75 mmol) in DMF (15 mL) was added naphthol 16 (1.00 g, 6.28 mmol) portionwise. The reaction mixture was warmed to RT over 15 min then cooled to 0 °C.…”