ABSTRACT
Prostaglandin antagonists, with their pharmacological effects, are well-known drugs capable of treating widely diffused illnesses, including pain and inflammation disorders. In recent years, a major research focus has been devoted to the identification of agents able to selectively antagonize each receptor with which prostaglandins interact. This review attempts to give a broad overview of molecules capable of selectively blocking the prostaglandin PGE2 EP4 receptor. Further therapeutic applications and uses have also been disccussed, including the first drug candidate to have reached clinical trials within the last few years.
Subject(s)
Prostaglandin Antagonists/pharmacology , Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors , Animals , Benzoates/pharmacology , Benzoates/therapeutic use , Humans , Prostaglandin Antagonists/therapeutic use , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Sulfonylurea Compounds/pharmacology , Sulfonylurea Compounds/therapeutic useABSTRACT
The construction of a EP(4) antagonists pharmacophore model and the discovery of a highly potent oxepinic series of EP(4) antagonists is discussed. Compound 1a exhibits an excellent selectivity profile toward EP(2) receptor subtype and low cytochrome P450 inhibition potential.
Subject(s)
Benzoxepins/chemical synthesis , Benzoxepins/pharmacology , Models, Molecular , Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors , Benzoxepins/chemistry , Drug Evaluation, Preclinical , Humans , In Vitro TechniquesABSTRACT
5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.
Subject(s)
Quinolones/chemistry , Receptors, Serotonin, 5-HT1/drug effects , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Animals , Autoreceptors/antagonists & inhibitors , Autoreceptors/drug effects , Quinolones/pharmacokinetics , Rats , Selective Serotonin Reuptake Inhibitors/pharmacology , Synapses/chemistryABSTRACT
Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Antidepressive Agents/chemical synthesis , Benzoxazines/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/pharmacology , Benzoxazines/pharmacokinetics , Benzoxazines/pharmacology , Callithrix , Cell Line , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme System/metabolism , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Guinea Pigs , Humans , In Vitro Techniques , Male , Microsomes, Liver/metabolism , Protein Binding , Radioligand Assay , Rats , Rats, Sprague-Dawley , Serotonin Plasma Membrane Transport Proteins/metabolism , Structure-Activity RelationshipABSTRACT
8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones have been identified as highly potent 5-HT(1A/B/D) receptor antagonists with and without additional SerT activity and a high degree of selectivity over hERG potassium channels. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.
Subject(s)
Benzoxazines/chemistry , Piperazines/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/chemistry , Animals , Benzoxazines/metabolism , Benzoxazines/pharmacology , CHO Cells , Cricetinae , Cricetulus , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Piperazines/metabolism , Piperazines/pharmacology , Rats , Receptors, Serotonin, 5-HT1/metabolism , Serotonin Antagonists/metabolism , Serotonin Antagonists/pharmacology , Selective Serotonin Reuptake Inhibitors/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacologyABSTRACT
Investigation of a series 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones has led to the discovery of potent 5-HT(1A/1B/1D) receptor antagonists with and without additional SerT affinity. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.
Subject(s)
Benzoxazoles/chemical synthesis , Piperazines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Benzoxazoles/pharmacology , Drug Design , Humans , Liver/drug effects , Liver/metabolism , Models, Chemical , Piperazine , Piperazines/chemistry , Piperazines/pharmacology , Rats , Serotonin 5-HT1 Receptor AntagonistsABSTRACT
The synthesis of a series of carbazole derivatives and their SAR at the NPY Y1 receptor is described. Modulation of physicochemical properties by appropriate decoration led to the identification of a high-affinity NPY Y1 antagonist that shows high brain penetration and modest oral bioavailability.
Subject(s)
Carbazoles/chemical synthesis , Carbazoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Biological Availability , Brain/drug effects , Brain/metabolism , CHO Cells , Carbazoles/pharmacokinetics , Chemical Phenomena , Chemistry, Physical , Cricetinae , Cricetulus , Half-Life , Indicators and Reagents , Male , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The SAR of a new series of tetrahydrocarbazole derivatives is described: the appropriate decoration of this template led to the identification of a new class of NPY-1 antagonists showing good in vitro potency and a promising in vivo pharmacokinetic profile in rat.
