ABSTRACT
A new series of morpholine derivatives has been identified as selective DA D3 receptor antagonists; their in vitro profile and pharmacokinetic data are provided.
Subject(s)
Dopamine D2 Receptor Antagonists/chemistry , Morpholines/chemistry , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Binding Sites , Dopamine D2 Receptor Antagonists/chemical synthesis , Dopamine D2 Receptor Antagonists/pharmacokinetics , Half-Life , Molecular Docking Simulation , Morpholines/chemical synthesis , Morpholines/pharmacokinetics , Protein Structure, Tertiary , Rats , Receptors, Dopamine D3/metabolismABSTRACT
A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.
Subject(s)
Pyrroles/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Triazoles/pharmacology , Animals , Binding, Competitive/drug effects , CHO Cells , Cricetulus , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , HEK293 Cells , Humans , Models, Molecular , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Novel series of pyrrole-pyrazinone and pyrazole-pyrazinone have been identified as potent and selective Vasopressin(1b) receptor antagonists. Exploration of the substitution pattern around the core of these templates allowed generation of compounds with high inhibitory potency at the Vasopressin(1b) receptor, including examples that showed good selectivity with respect to Vasopressin(1a), Vasopressin(2), and Oxytocin receptor subtypes.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Pyrazines/pharmacology , Pyrroles/pharmacology , Pyrazines/chemistry , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases. A few derivatives with overall favorable developability characteristics were selected for further late lead optimization studies.
Subject(s)
Heptanes/chemistry , Heptanes/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Animals , CHO Cells , Cricetulus , Crystallography, X-Ray , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Models, Molecular , Receptors, Dopamine D3/metabolism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes with high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles was recently reported. We also recently discussed the role of the linker associated with the triazole moiety. In this manuscript, we are reporting a detailed exploration of the region of the receptor interacting with the amine terminus of the scaffold wherein SAR and developability data associated with these novel templates was undertaken.