ABSTRACT
Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.
Subject(s)
Arginine/analogs & derivatives , Flavones/chemistry , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Animals , Arginine/chemical synthesis , Arginine/chemistry , Arginine/pharmacology , Brain/metabolism , Caco-2 Cells , Cell Membrane Permeability , Feeding Behavior/drug effects , Flavones/chemical synthesis , Flavones/pharmacology , HEK293 Cells , Humans , Male , Membranes, Artificial , Mice, Knockout , Microsomes, Liver/metabolism , Mutation , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/genetics , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/pharmacokinetics , Serotonin 5-HT2 Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic ß-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.
Subject(s)
Drug Discovery , Hypoglycemic Agents/pharmacology , Molecular Targeted Therapy , Pyridones/pharmacology , Receptors, G-Protein-Coupled/metabolism , Sulfones/pharmacology , Animals , Clinical Trials as Topic , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Drug Design , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Male , Mice , Models, Molecular , Protein Conformation , Pyridones/chemistry , Pyridones/pharmacokinetics , Pyridones/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/chemistry , Sulfones/chemistry , Sulfones/pharmacokinetics , Sulfones/therapeutic useABSTRACT
Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.
Subject(s)
Benzofurans/pharmacology , Receptors, G-Protein-Coupled/agonists , Benzofurans/chemical synthesis , Benzofurans/chemistry , Cell Line , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.
Subject(s)
Isoquinolines/pharmacology , Pyrazines/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Eating/drug effects , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Models, Molecular , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT(2C) agonism with excellent selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , Isoquinolines/chemistry , Pyrroles/chemistry , Pyrroles/chemical synthesis , Receptor, Serotonin, 5-HT2C/chemistry , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Animals , Half-Life , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Humans , Isoquinolines/chemical synthesis , Isoquinolines/pharmacokinetics , Male , Pyrroles/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A/chemistry , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/chemistry , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/chemistry , Serotonin 5-HT2 Receptor Agonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.