ABSTRACT
The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.
Subject(s)
Anti-Obesity Agents/administration & dosage , Anti-Obesity Agents/pharmacology , Benzodioxoles/administration & dosage , Benzodioxoles/pharmacology , Obesity/drug therapy , Receptor, Cannabinoid, CB1/agonists , Animals , Anti-Obesity Agents/chemistry , Benzodioxoles/chemical synthesis , Benzodioxoles/chemistry , Body Weight/drug effects , Crystallography, X-Ray , Cyclohexanols/antagonists & inhibitors , Cyclohexanols/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Design , Humans , Hypothermia/chemically induced , Ligands , Male , Mice , Microsomes/drug effects , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/chemistry , Structure-Activity RelationshipABSTRACT
The asymmetric synthesis and receptor pharmacology of (1S,2R,3R,5R,6S)-2-amino-3-Hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (+)-9 (HYDIA) and a few of its O-alkylated derivatives are described. The key step of the synthesis utilizes Sharpless' asymmetric dihydroxylation (AD-beta) for the kinetic resolution of a bicyclic racemic precursor olefin. In contrast to the bicyclic glutamate analogue LY354740, which is a potent and selective agonist for the group II metabotropic glutamate receptors (mGluRs), these new conformationally restricted and also hydroxylated or alkoxylated glutamate analogues are potent and selective antagonists for the group II mGluRs.
Subject(s)
Bridged Bicyclo Compounds/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Receptors, Metabotropic Glutamate/agonists , Alkylation , Animals , Binding, Competitive , Bridged Bicyclo Compounds/chemical synthesis , Excitatory Amino Acid Agonists/chemical synthesis , Glutamic Acid/chemistry , Glutamic Acid/pharmacology , Hydroxylation , Ligands , Mice , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Screening of the Roche compound depository led to the identification of (1-benzyloxy-4,5-dihydro-1H-imidazol-2-yl)-butyl amine 4, a structurally novel NR1/2B subtype selective NMDA receptor antagonist. The structure-activity relationships developed in this series resulted in the discovery of a novel class of potent and selective NMDA receptor blockers displaying activity in vivo.
Subject(s)
Excitatory Amino Acid Antagonists/chemistry , Imidazoles/chemistry , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Cells, Cultured , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/pharmacology , Imidazoles/administration & dosage , Imidazoles/pharmacology , Injections, Intraperitoneal , Mice , Mice, Inbred DBA , Potassium Channels, Voltage-Gated/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/physiology , Seizures/prevention & controlABSTRACT
A series of 4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and analogous quinolines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. 2-Hydroxyalkylamino substitution combines high affinity with selectivity (vs alpha1 and M1 receptors) and activity in vivo.
Subject(s)
Pyridines/chemical synthesis , Quinolines/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Mice , Pyridines/pharmacology , Quinolines/pharmacology , Seizures/drug therapy , Structure-Activity RelationshipABSTRACT
Recently, we disclosed 4-aminoquinolines as structurally novel NR1/2B subtype selective NMDA receptor antagonists. We would now like to report our findings on structurally related pyridine analogues. The SAR developed in this series resulted in the discovery of high affinity antagonists which are selective (vs alpha1 and M1 receptors) and active in vivo.
Subject(s)
Isoquinolines/chemistry , Isoquinolines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Acoustic Stimulation , Animals , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Hydrogen-Ion Concentration , Mice , Mice, Inbred DBA , Seizures/etiology , Seizures/prevention & control , Structure-Activity RelationshipABSTRACT
Discovery of novel antimicrobial agents effective against infections caused by drug-resistant pathogens is an important objective. In order to find a new parenteral carbapenem antibiotic, which has potent antibacterial activity especially against methicillin-resistant staphylococci, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae, a series of 1beta-methylcarbapenems with thiazol-2-ylthio groups at the C-2 position have been synthesized. Structure-activity relationships were investigated which led to SM-197436 (27), SM-232721 (44) and SM-232724 (41), being selected for further evaluation.
Subject(s)
Anti-Bacterial Agents , Carbapenems , Enterococcus/drug effects , Methicillin Resistance , Staphylococcus aureus/drug effects , Vancomycin Resistance , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Carbapenems/chemical synthesis , Carbapenems/chemistry , Carbapenems/pharmacology , Humans , Microbial Sensitivity Tests/methods , Penicillin Resistance , Streptococcus pneumoniae/drug effects , Structure-Activity RelationshipABSTRACT
Screening of the Roche compound library led to the identification of 4-aminoquinoline 4 as structurally novel NR1/2B subtype selective NMDA receptor antagonist. The SAR which was developed in this series resulted in the discovery of highly potent and in vivo active blockers.
