ABSTRACT
Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.
Subject(s)
Drug Discovery , Orexin Receptor Antagonists , Pyridines/pharmacology , Sleep Initiation and Maintenance Disorders/drug therapy , Thiazoles/pharmacology , Animals , Dogs , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
We have identified and synthesized a series of diaryl substituted pyrazoles as potent antagonists of the chemokine receptor subtype 2. Structure-activity relationship studies directed toward improving the potency led to the discovery of 23 (IC50 = 6 nM).
Subject(s)
Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Chemotaxis/drug effects , Humans , In Vitro Techniques , Indicators and Reagents , Monocytes/drug effects , Oxidation-Reduction , Receptors, CCR2 , Receptors, Chemokine/drug effects , Structure-Activity RelationshipABSTRACT
We have identified and synthesized a brain penetrant propanoic acid as an allosteric potentiator of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency, level of potentiation and brain penetration led to the discovery of 8 (EC50=1200 nM, 77% potentiation, 119% brain/plasma in rat, 20 mpk i.p., brain level of 5700 nM).
Subject(s)
Brain/physiology , Butanes/chemical synthesis , Butanes/pharmacology , Propionates/chemical synthesis , Propionates/pharmacology , Receptors, Metabotropic Glutamate/physiology , Allosteric Regulation , Animals , Brain/drug effects , Butanes/pharmacokinetics , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Kinetics , Molecular Conformation , Phenyl Ethers , Propionates/pharmacokinetics , Rats , Receptors, Metabotropic Glutamate/drug effects , Structure-Activity RelationshipABSTRACT
We have identified and synthesized a series of phenyl-tetrazolyl and 4-thiopyridyl indanones as allosteric potentiators of the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of potentiation, as well as PK properties, led to the discovery of 28 (EC50=186 nM), which displayed activity in a rodent model for schizophrenia.
Subject(s)
Indans/pharmacology , Receptors, Metabotropic Glutamate/agonists , Allosteric Regulation , Animals , Brain/metabolism , Disease Models, Animal , Indans/pharmacokinetics , Models, Chemical , Molecular Structure , Protein Binding , Rats , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
We have identified and synthesized a series of 4-thiopyridyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward replacement of the tetrazole in the initial lead led to the discovery of 16 (EC(50)=340 nM), which showed improved brain penetration over the initial lead.
Subject(s)
Acetophenones/metabolism , Pyridines/chemistry , Pyridines/metabolism , Receptors, Metabotropic Glutamate/metabolism , Acetophenones/chemistry , Allosteric Regulation/physiology , Animals , Brain/metabolism , Cell Line , Humans , Protein Binding/physiology , Rats , Receptors, Metabotropic Glutamate/agonists , Structure-Activity Relationship , TetrazolesABSTRACT
We have identified and synthesized a series of aryl-tetrazoyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of potentiation led to the discovery of 22 (EC(50)=93nM, 128% potentiation).