ABSTRACT
Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gαq-coupled partial agonist, compound 1 is a dual Gαq and Gαs-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), γ-linolenic acid, can be computationally modeled in this site. Both γ-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/pharmacology , Incretins/metabolism , Insulin Secretion , Receptors, G-Protein-Coupled/agonists , Allosteric Site/genetics , Animals , Benzofurans/pharmacology , Benzofurans/therapeutic use , Crystallography, X-Ray , Diabetes Mellitus, Type 2/metabolism , Drug Synergism , HEK293 Cells , Humans , Hypoglycemic Agents/therapeutic use , Insulin/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Knockout , Molecular Docking Simulation , Mutagenesis, Site-Directed , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sulfones/pharmacology , Sulfones/therapeutic use , gamma-Linolenic Acid/metabolismABSTRACT
To develop novel treatments for type 2 diabetes and dyslipidemia, we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma ceramides in rodents, have a slight trend toward enhanced insulin sensitization in DIO mice, and reduce triglycerides and raise HDL in cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.
Subject(s)
Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Serine C-Palmitoyltransferase/antagonists & inhibitors , Administration, Oral , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Imidazoles/administration & dosage , Imidazoles/chemistry , MCF-7 Cells , Male , Mice , Mice, Obese , Molecular Structure , Piperidines/administration & dosage , Piperidines/chemistry , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyridines/administration & dosage , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Serine C-Palmitoyltransferase/metabolism , Structure-Activity RelationshipABSTRACT
The farnesoid X receptor (FXR) is a member of the "metabolic" subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, we have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr-/- mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This molecule is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclinical species. The preclinical ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biological profile of this molecule is discussed.
Subject(s)
Dyslipidemias/drug therapy , Hypolipidemic Agents/chemistry , Indoles/chemistry , Isoxazoles/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Cholesterol/blood , Dogs , Double-Blind Method , Female , HEK293 Cells , Humans , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Indoles/pharmacokinetics , Indoles/pharmacology , Isoxazoles/pharmacokinetics , Isoxazoles/pharmacology , Macaca fascicularis , Male , Mice , Mice, Knockout , Rats , Rats, Sprague-Dawley , Receptors, LDL/genetics , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
The design, synthesis, and structure activity relationships for a novel series of indoles as potent, selective, thyroid hormone receptor ß (TRß) agonists is described. Compounds with >50× binding selectivity for TRß over TRα were generated and evaluation of compound 1c from this series in a model of dyslipidemia demonstrated positive effects on plasma lipid endpoints in vivo.
Subject(s)
Acetates/pharmacology , Drug Design , Indoles/pharmacology , Thyroid Hormone Receptors beta/agonists , Acetates/chemical synthesis , Acetates/chemistry , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
A novel series of 2-aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides have been identified as potent antivirals against human herpesviruses. These compounds demonstrate broad-spectrum inhibition of the herpesvirus polymerases HCMV, HSV-1, EBV, and VZV with high specificity compared to human DNA polymerases.
Subject(s)
Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Enzyme Inhibitors/pharmacology , Ethylamines/pharmacology , Exodeoxyribonucleases/antagonists & inhibitors , Herpesviridae/drug effects , Herpesvirus 1, Human/drug effects , Herpesvirus 4, Human/drug effects , Nucleic Acid Synthesis Inhibitors , Pyridines/pharmacology , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/therapeutic use , Binding, Competitive , DNA-Directed DNA Polymerase , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Ethylamines/chemical synthesis , Herpes Zoster/drug therapy , Herpesviridae/enzymology , Humans , Models, Chemical , Pyridines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The oxazolidinones are promising agents for the treatment of infections caused by gram-positive bacteria, including multidrug-resistant strains. In ongoing studies we have discovered that a strategically placed chiral center of appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone analogues (gram-positive MIC's<0.5 microg/mL for the most potent congeners). The design, synthesis, antibacterial activity and pharmacokinetic profile of a selected series of alpha-methylated indoline derivatives and a related set of tetrahydroquinolyl and dihydrobenzoxazinyl analogues are discussed.