ABSTRACT
Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.
Subject(s)
Oxazoles/chemical synthesis , Pyridones/chemical synthesis , Receptors, Prostaglandin E, EP3 Subtype/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Humans , Molecular Structure , Oxazoles/chemistry , Oxazoles/pharmacology , Protein Binding/drug effects , Pyridones/chemistry , Pyridones/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Prostaglandin E, EP3 Subtype/chemistry , Structure-Activity RelationshipABSTRACT
A series of 3-urea-1-(phenylmethyl)-pyridones was discovered as novel EP(3) antagonists via high-throughput screening and subsequent optimization. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in potent and selective EP(3) receptor antagonists such as 11g are described.
Subject(s)
Pyridones/pharmacology , Receptors, Prostaglandin E, EP3 Subtype/antagonists & inhibitors , Animals , Humans , Pyridones/chemistry , Rats , Structure-Activity RelationshipABSTRACT
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 EP3 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 EP3 antagonists are excellent tool compounds for investigating and validating potential therapeutic benefits from selectively inhibiting the EP3 receptor.
