ABSTRACT
Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.
Subject(s)
Anemia , Hypoxia-Inducible Factor-Proline Dioxygenases , Macaca fascicularis , Prolyl-Hydroxylase Inhibitors , Animals , Anemia/drug therapy , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Administration, Oral , Humans , Prolyl-Hydroxylase Inhibitors/pharmacology , Prolyl-Hydroxylase Inhibitors/chemistry , Prolyl-Hydroxylase Inhibitors/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Erythropoietin , Drug Discovery , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesisABSTRACT
Motilin is a 22-amino-acid gastrointestinal (GI) hormone and is involved in the regulation of GI motility through binding to GPR38, the motilin receptor which is expressed on smooth muscle cells in the GI tract. Therefore, GPR38 agonists are expected to be novel gastrointestinal prokinetic agents for the treatment of functional gastrointestinal disorders such as gastroparesis and chronic constipation. We identified a series of N-methylanilide derivatives as novel non-macrolide GPR38 agonists. Among them, 12 di-l-tartrate (DS-3801b) was selected as a clinical candidate for further evaluation.
Subject(s)
Aniline Compounds/pharmacology , Cyclohexanes/pharmacology , Drug Discovery , Gastrointestinal Agents/pharmacology , Gastroparesis/drug therapy , Piperazines/pharmacology , Receptors, G-Protein-Coupled/agonists , Aniline Compounds/chemistry , Animals , Cyclohexanes/chemical synthesis , Cyclohexanes/chemistry , Dose-Response Relationship, Drug , Gastrointestinal Agents/chemical synthesis , Gastrointestinal Agents/chemistry , Gastroparesis/metabolism , Humans , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Rabbits , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
We identified (5R)-6-methyl-5-phenyl-1,3,4,5,6,7-hexahydro-2,5-methano-2,6-benzodiazonine (DS21980956: 4-(R)) as a novel [5.2.1]bicyclic basic compound. The scaffold was inspired by fentanyl or pethidine, which possess potent analgesic activities. DS21980956 had potent analgesic activity in the mouse acetic acid writhing test or tail flick test without agonistic activity at the µ opioid receptor (MOR). The mechanism of analgesic action of DS21980956 was considered to differ from a biased ligand, for example, TRV-130 (3, oliceridine).
Subject(s)
Amines/therapeutic use , Analgesics/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Pain/drug therapy , Acetic Acid , Amines/chemistry , Analgesics/chemistry , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Dose-Response Relationship, Drug , Mice , Mice, Inbred Strains , Molecular Structure , Pain/chemically induced , Pain Measurement , Structure-Activity RelationshipABSTRACT
GPR40 agonists stimulate insulin secretion only under the presence of high glucose concentration. Based on this mechanism, GPR40 agonists are believed to be promising novel insulin secretagogues with low risk of hypoglycemia. The optimizations of 3-aryl-3-ethoxypropanoic acids were performed to improve in vitro activity. We discovered compound 29r (DS-1558), (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, which was confirmed to have an enhancing effect on glucose-dependent insulin secretion after intravenous glucose injection in SD rats.
Subject(s)
Indans/metabolism , Phenylpropionates/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Humans , Hypoglycemic Agents , Molecular Structure , RatsABSTRACT
The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic ß cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with a low risk of hypoglycemia.
Subject(s)
Drug Discovery , Propionates/pharmacology , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Blood Glucose/drug effects , Dose-Response Relationship, Drug , Glucose Tolerance Test , Humans , Molecular Structure , Propionates/administration & dosage , Propionates/chemistry , Rats , Rats, Inbred F344 , Rats, Zucker , Structure-Activity RelationshipABSTRACT
GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic ß-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, as a potent and orally available GPR40 agonist. Compound 13 (DS-1558) was found to have potent glucose lowering effects during an oral glucose tolerance test in ZDF rats.
ABSTRACT
G protein-coupled receptor 40 (GPR40) is a Gq-coupled receptor for free fatty acids predominantly expressed in pancreatic ß-cells. In recent years, GPR40 agonists have been investigated for use as novel therapeutic agents in the treatment of type 2 diabetes. We discovered a novel small molecule GPR40 agonist, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (DS-1558). The GPR40-mediated effects of DS-1558 on glucose-stimulated insulin secretion were evaluated in isolated islets from GPR40 knock-out and wild-type (littermate) mice. The GPR40-mediated effects on glucose tolerance and insulin secretion were also confirmed by an oral glucose tolerance test in these mice. Furthermore, oral administration of DS-1558 (0.03, 0.1 and 0.3mg/kg) significantly and dose-dependently improved hyperglycemia and increased insulin secretion during the oral glucose tolerance test in Zucker fatty rats, the model of insulin resistance and glucose intolerance. Next, we examined the combination effects of DS-1558 with glucagon like peptide-1 (GLP-1). DS-1558 not only increased the glucose-stimulated insulin secretion by GLP-1 but also potentiated the maximum insulinogenic effects of GLP-1 after an intravenous glucose injection in normal Sprague Dawley rats. Furthermore, the glucose lowering effects of exendin-4, a GLP-1 receptor agonist, were markedly potentiated by the DS-1558 (3mg/kg) add-on in diabetic db/db mice during an intraperitoneal glucose tolerance test. In conclusion, our results indicate that add-on GPR40 agonists to GLP-1 related agents might be a potential treatment compared to single administration of these compounds. Therefore the combinations of these agents are a novel therapeutic option for type 2 diabetes.