ABSTRACT
2-Piperidones were prepared bearing heptanoic acid or a thioether heptanoic acid at the 1-position as well as appropriately substituted at the 6-position to mimic the structure of prostaglandins. The stereochemical purity at the 6-position was determined to be 95% ee for an advanced synthetic intermediate. The 2-piperidones were identified as potent agonists at the EP4 prostanoid receptor. They displayed a high affinity (Ki 5-130 nM) at EP4 and subtype selectivity.
Subject(s)
Lactams/pharmacology , Piperidones/pharmacology , Receptors, Prostaglandin E/agonists , Lactams/chemistry , Ligands , Piperidones/chemistry , Receptors, Prostaglandin E, EP4 SubtypeABSTRACT
Two distinct synthetic schemes were applied to access heteroatom-containing alpha-chain lactams or lactams terminated as aryl acids. The latter lactams were devised using a pharmacophore for EP(4) receptor activity. gamma-Lactams were characterized for their prostanoid EP receptor affinities and EP(4) activity and found to be selective for the EP(2) and EP(4) receptors or selective for the EP(4) subtype. Benzoic acid 17 displayed enhanced in vivo exposure relative to 3.
Subject(s)
Benzoates/chemical synthesis , Lactams/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Prostaglandin E/agonists , Animals , Benzoates/pharmacokinetics , Benzoates/pharmacology , Blood Proteins/metabolism , Half-Life , Humans , Lactams/pharmacokinetics , Lactams/pharmacology , Models, Molecular , Molecular Conformation , Monte Carlo Method , Oxidation-Reduction , Protein Binding , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Receptors, Prostaglandin E/metabolism , Receptors, Prostaglandin E, EP2 Subtype , Receptors, Prostaglandin E, EP4 Subtype , Structure-Activity RelationshipABSTRACT
A series of 7-[(5R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were prepared, their isomeric purity determined, and pharmacologically evaluated. Lactams with affinity for the EP(4) receptor displayed agonist behavior. The lower side-chain of the lactam template could be substituted to afford ligands (e.g., 17, 24, 30, 31, and 33) of high potency and greater than 1000-fold affinity for EP(4) versus the other EP prostanoid receptors.
