ABSTRACT
A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.
Subject(s)
Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Animals , Dose-Response Relationship, Drug , Humans , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Rats , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2CR agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
Subject(s)
Benzodiazepines/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Animals , Benzodiazepines/chemical synthesis , Benzodiazepines/metabolism , Benzodiazepines/pharmacokinetics , Dogs , Drug Discovery , Drug Stability , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/metabolism , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Humans , Macaca fascicularis , Male , Mice , Microsomes/metabolism , Molecular Structure , Rats, Sprague-Dawley , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
Subject(s)
Amines/pharmacology , Quinolines/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Administration, Oral , Amines/administration & dosage , Amines/chemistry , Animals , Dose-Response Relationship, Drug , Male , Molecular Structure , Quinolines/administration & dosage , Quinolines/chemistry , Rats , Rats, Sprague-Dawley , Serotonin 5-HT2 Receptor Agonists/administration & dosage , Serotonin 5-HT2 Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin 5-HT2 Receptor Antagonists/chemistry , Serotonin 5-HT2 Receptor Antagonists/therapeutic use , Sleep Initiation and Maintenance Disorders/drug therapy , Sleep/drug effects , Animals , Humans , Rats , Serotonin 5-HT2 Receptor Antagonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT(2A) receptor. 5-HT(2A) receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT(2A) receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC(50) = 8.7 nM and had negligible binding affinity for the closely related 5-HT(2B) and 5-HT(2C) receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.
Subject(s)
Arteries/drug effects , Benzamides/chemistry , Benzamides/pharmacology , Drug Discovery/methods , Drug Inverse Agonism , Morpholines/chemistry , Morpholines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Serotonin 5-HT2 Receptor Agonists , Thrombosis/drug therapy , Animals , Benzamides/metabolism , Benzamides/pharmacokinetics , Dogs , Female , Humans , Inhibitory Concentration 50 , Male , Morpholines/metabolism , Morpholines/pharmacokinetics , Platelet Aggregation/drug effects , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Rats , Receptor, Serotonin, 5-HT2A/metabolism , Structure-Activity Relationship , Substrate Specificity , Thrombosis/metabolismABSTRACT
Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.