ABSTRACT
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemistry , Pyrimidinones/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Thiophenes/chemistry , Administration, Oral , Animals , Chronic Pain/drug therapy , Disease Models, Animal , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Pyrimidinones/chemical synthesis , Pyrimidinones/therapeutic use , Rats , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/therapeutic useABSTRACT
Complex tetracyclic sulfones were designed as gamma-secretase inhibitors and a stereoselective synthesis was achieved. Gamma-secretase activity was seen predominately in the (-) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Sulfones/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Drug Design , Hepatocytes/metabolism , Humans , Mice , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacologyABSTRACT
Tricyclic sulfones were designed as gamma-secretase inhibitors and found to have excellent potency. Extensive SAR shows that a large number of sulfonamides at position 7 of the tricycle are very well tolerated. Compounds such as 15a and 15c showed remarkable in vivo potency.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Sulfones/chemistry , Sulfones/pharmacology , Administration, Oral , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/blood , Animals , Brain Chemistry/drug effects , Mice , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfones/chemical synthesisABSTRACT
A-ring modifications on the triazafluorenone core structure were investigated. Five membered heterocycles such as pyrazoles and isothiazoles are not tolerated. It has been found that the pyrimidine nucleus was very well tolerated on the left hand side. Amino pyrimidine compounds 24 and 27 showed acceptable PK profile with significant brain penetration. Compound 9 served as a versatile intermediate for a number of chemical transformations.
Subject(s)
Aza Compounds/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Humans , Molecular StructureABSTRACT
A series of novel benzazepine derived dopamine D(1) antagonists have been discovered. These compounds are highly potent at D(1) and showed excellent selectivity over D(2) and D(4) receptors. SAR studies revealed that a variety of functional groups are tolerated on the D-ring of known tetracyclic benzazepine analog 2, SCH 39166, leading to compounds with nanomolar potency at D(1) and good selectivity over D(2)-like receptors.
Subject(s)
Benzazepines/chemistry , Dopamine Antagonists/chemistry , Receptors, Dopamine D1/antagonists & inhibitors , Animals , Benzazepines/pharmacology , Dopamine Antagonists/pharmacology , Male , Protein Binding/drug effects , Protein Binding/physiology , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/physiologyABSTRACT
A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.
Subject(s)
Benzazepines/chemistry , Benzazepines/pharmacology , Dopamine Antagonists/chemistry , Dopamine Antagonists/pharmacology , Receptors, Dopamine D1/antagonists & inhibitors , Animals , Rats , Receptors, Dopamine D1/physiologyABSTRACT
Introduction of small unsaturated alkylamino groups at the 4-position of the A-ring of the tricyclic framework (triazafluorenone) afforded extremely potent and selective mGluR1 antagonists with desirable properties. Compounds 11q and 11s are active in the SNL pain model with ED(50)s 3.3 and 6.4 mg/kg respectively. Metabolic outcome of propargyl amino moiety was studied.
Subject(s)
Neuralgia/drug therapy , Pyridines/chemistry , Pyrimidines/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Administration, Oral , Animals , Dose-Response Relationship, Drug , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Inhibitory Concentration 50 , Pyridines/pharmacology , Pyrimidines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A series of novel aminobenzimidazoles was prepared and evaluated for h-MCH-R1 antagonist properties. Most of the compounds showed excellent h-MCH-R1 binding affinity as well as mouse ex vivo binding. Compounds 9 and 18 were active in mouse DIO studies at 30mpk.
Subject(s)
Anti-Obesity Agents/pharmacology , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Metabolic Diseases/drug therapy , Receptors, Somatostatin/antagonists & inhibitors , Animals , Anti-Obesity Agents/chemistry , Benzimidazoles/chemistry , Binding, Competitive/drug effects , Diet , Disease Models, Animal , Drug Evaluation, Preclinical , Eating/drug effects , Humans , Mice , Mice, Obese , Molecular Conformation , Obesity/drug therapy , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Acylated and aroylated hydrazinoclozapines are highly potent dopamine D(1) antagonists that show remarkable selectivity over other dopamine receptors. The most potent compound in this series is the 2,6-dimethoxybenzhydrazide 33 with a D(1)K(i) of 1.6 nM and 212-fold selectivity over D(2) receptor.
Subject(s)
Clozapine/chemistry , Clozapine/pharmacology , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Hydrazines/chemistry , Receptors, Dopamine D1/antagonists & inhibitors , Clozapine/chemical synthesis , Clozapine/classification , Dopamine Antagonists/chemistry , Dopamine Antagonists/classification , Dopamine D2 Receptor Antagonists , Molecular Structure , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Structure-Activity RelationshipABSTRACT
A series of potent and selective inhibitors of h-MCH-R1 has been developed based on the piperidine glycineamide compounds I and II. These structurally more rigid tetrahydroisoquinolines (III and IV) showed better pharmacokinetics. The highly potent compounds 12d and 12g displayed excellent rat pk.
