ABSTRACT
The discovery and characterization of novel naphthyridine derivatives with selective α5-GABAAR negative allosteric modulator (NAM) activity are disclosed. Utilizing a scaffold-hopping strategy, fused [6 + 6] bicyclic scaffolds were designed and synthesized. Among these, 1,6-naphthyridinones were identified as potent and selective α5-GABAAR NAMs with metabolic stability, cardiac safety, and beneficial intellectual property (IP) issues. Relocation of the oxo acceptor function and subsequent modulation of the physicochemical properties resulted in novel 1,6-naphthyridines with improved profile, combining good potency, selectivity, ADME, and safety properties. Besides this, compound 20, having the most balanced profile, provided in vivo proof of concept (POC) for the new scaffold in two animal models of cognitive impairment associated with schizophrenia (CIAS).
Subject(s)
Receptors, GABA-A , Schizophrenia , Allosteric Regulation , Animals , Naphthyridines/pharmacology , Naphthyridines/therapeutic use , Receptors, GABA-A/metabolism , Schizophrenia/drug therapy , gamma-Aminobutyric AcidABSTRACT
Within the framework of orthosteric G protein coupled receptor (GPCR) polypharmacology herein we report the systematic elaboration and thorough evaluation of a data matrix generated by sampling the chemical space around a common 5,6-fused bicyclic heteroaromatic template applying characteristic pharmacophore elements of central nervous system (CNS) relevant aminergic GPCR ligands.
Subject(s)
Indoles/chemistry , Ligands , Humans , Indoles/metabolism , Protein Binding , Receptors, Dopamine D2/chemistry , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/chemistry , Receptors, Dopamine D3/metabolism , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Receptors, Histamine H3/chemistry , Receptors, Histamine H3/metabolism , Receptors, Serotonin/chemistry , Receptors, Serotonin/metabolism , Structure-Activity RelationshipABSTRACT
As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed.
Subject(s)
Ligands , Receptor, Serotonin, 5-HT2A/chemistry , Receptor, Serotonin, 5-HT2C/chemistry , Serotonin Plasma Membrane Transport Proteins/chemistry , Animals , Humans , Liver/drug effects , Liver/metabolism , Mice , Permeability/drug effects , Piperazines/chemistry , Piperazines/pharmacology , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
This Letter describes our attempts to elaborate dually acting compounds possessing serotonin re-uptake transporter inhibitor and serotonin 5-HT2C receptor antagonist properties. A novel series of 1,3-diphenylureas and N-phenylbenzamides have thus been prepared and evaluated. Based on its in vitro and in vivo activities, as well as pharmacokinetic profile, compound 16a was identified as a lead compound. The synthesis and structure-activity relationship of this series of compounds is presented herein.
