ABSTRACT
A novel series of decahydroquinoline CB2 agonists is described. Optimization of the amide substituent led to improvements in CB2/CB1 selectivity as well as physical properties. Two key compounds were examined in the rat CFA model of acute inflammatory pain. A moderately selective CB2 agonist was active in this model. A CB2 agonist lacking functional CB1 activity was inactive in this model despite high in vivo exposure both peripherally and centrally.
Subject(s)
Amides/chemistry , Analgesics/chemistry , Quinolines/chemistry , Receptor, Cannabinoid, CB2/agonists , Amides/chemical synthesis , Amides/therapeutic use , Analgesics/chemical synthesis , Analgesics/therapeutic use , Animals , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Pain/drug therapy , Rats , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood-brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited (125)I-NPS binding in the CNS when administered to rats.
Subject(s)
Receptors, Neuropeptide/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Blood-Brain Barrier/metabolism , Central Nervous System/metabolism , Humans , Iodine Radioisotopes/chemistry , Protein Binding , Quinolones/chemical synthesis , Quinolones/chemistry , Quinolones/pharmacology , Rats , Receptors, Neuropeptide/metabolism , Structure-Activity RelationshipABSTRACT
Potent, novel 7-oxo alpha(v)beta3 antagonists have been prepared. These antagonists offer decreased plasma protein binding and excellent pharmacokinetic profiles.
Subject(s)
Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Integrin alphaVbeta3/antagonists & inhibitors , Animals , Dogs , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Models, Chemical , Molecular Structure , Oligopeptides , Osteoporosis/drug therapy , Structure-Activity RelationshipABSTRACT
3(S)-(6-methoxypyridin-3-yl)-3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propyl]imidazolidin-1-yl]propionic acid 6 was identified as a potent and selective antagonist of the alpha(v)beta(3) receptor. This compound has an excellent in vitro profile (IC(50) = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.
