ABSTRACT
Alterations in cardiac energy metabolism after a myocardial infarction contribute to the severity of heart failure (HF). Although fatty acid oxidation can be impaired in HF, it is unclear if stimulating fatty acid oxidation is a desirable approach to treat HF. Both immediate and chronic malonyl coenzyme A decarboxylase inhibition, which decreases fatty acid oxidation, improved cardiac function through enhancing cardiac efficiency in a post-myocardial infarction rat that underwent permanent left anterior descending coronary artery ligation. The beneficial effects of MCD inhibition were attributed to a decrease in proton production due to an improved coupling between glycolysis and glucose oxidation.
ABSTRACT
A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.
Subject(s)
Hyperparathyroidism, Secondary/drug therapy , Thiazoles/chemistry , Thiazoles/therapeutic use , Urea/analogs & derivatives , Administration, Oral , Animals , Biological Availability , Half-Life , Hyperparathyroidism, Secondary/metabolism , Hyperparathyroidism, Secondary/pathology , Male , Parathyroid Hormone/metabolism , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Calcium-Sensing/chemistry , Receptors, Calcium-Sensing/metabolism , Thiazoles/pharmacokineticsABSTRACT
The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of ß-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents.
Subject(s)
Biphenyl Compounds/pharmacology , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Biological Availability , Biphenyl Compounds/administration & dosage , Biphenyl Compounds/chemistry , Dose-Response Relationship, Drug , Mice , Mice, Knockout , Molecular Structure , Receptors, G-Protein-Coupled/deficiency , Receptors, G-Protein-Coupled/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model.
Subject(s)
Benzylamines/chemistry , Benzylamines/pharmacology , Parathyroid Hormone/antagonists & inhibitors , Parathyroid Hormone/blood , Receptors, Calcium-Sensing/metabolism , Administration, Oral , Animals , Benzylamines/administration & dosage , Benzylamines/pharmacokinetics , Male , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We report that the asthma drugs cromolyn disodium and nedocromil sodium are potent G-protein-coupled receptor 35 (GPR35) agonists. We utilized calcium flux and inositol phosphate accumulation assays to examine the pharmacology of these asthma drugs on the human, mouse and rat GPR35. The compounds were more potent on the human GPR35 than on mouse and rat receptors. In contrast, zaprinast, a known GPR35 agonist, was more potent on mouse and rat GPR35 than the human ortholog. We show by quantitative PCR that GPR35 is expressed in human mast cells, human basophils and human eosinophils. We also demonstrate that GPR35 mRNA is upregulated upon challenge with IgE antibodies. We show that, unlike zaprinast, a potent phosphodiesterase 5 (PDE5) inhibitor, cromolyn disodium and nedocromil sodium lack inhibitory activity towards PDE5. These findings suggest that GPR35 may play an important role in mast cell biology and be a potential target for the treatment of asthma.
Subject(s)
Anti-Asthmatic Agents/pharmacology , Cromolyn Sodium/pharmacology , Nedocromil/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Basophils/drug effects , Basophils/metabolism , Cricetinae , Drug Delivery Systems , Eosinophils/drug effects , Eosinophils/metabolism , Humans , Immunoglobulin E/pharmacology , In Vitro Techniques , Mast Cells/drug effects , Mast Cells/metabolism , Mice , Phosphodiesterase 5 Inhibitors/pharmacology , Purinones/pharmacology , RNA, Messenger/biosynthesis , Rats , Receptors, G-Protein-Coupled/biosynthesisABSTRACT
Our efforts to discover potent, orally bioavailable type II calcimimetic agents for the treatment of secondary hyperparathyroidism focused on the development of ring constrained analogues of the known calcimimetic R-568. The structure-activity relationships of various substituted heterocycles and their effects on the human calcium-sensing receptor are discussed. Pyrazole 15 was shown to be efficacious in a rat in vivo pharmacodynamic model.
Subject(s)
Aniline Compounds/chemical synthesis , Methylamines/chemical synthesis , Pyrazoles/chemical synthesis , Receptors, Calcium-Sensing/agonists , Administration, Oral , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Biological Availability , Cell Line , Crystallography, X-Ray , Humans , Hyperparathyroidism, Secondary/drug therapy , Male , Methylamines/chemistry , Methylamines/pharmacology , Molecular Structure , Parathyroid Hormone/blood , Phenethylamines , Propylamines , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Calcium-Sensing/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Nicotinic acid has been used for several decades to treat dyslipidemia. In mice, the lipid-lowing effect of nicotinic acid is mediated by the Gi coupled receptor PUMA-G. In humans, high (GPR109A) and low (GPR109B) affinity nicotinic acid receptors have been characterized. Here we identify monomethylfumarate as a GPR109A agonist. Monomethylfumarate is the active metabolite of the psoriasis drug Fumaderm. We show that monomethylfumarate activates GPR109A in a calcium based aequorin assay, cAMP assay and demonstrate competitive binding with nicotinic acid. We show that GPR109A is highly expressed in neutrophils and epidermal keratinocytes, and that its expression is increased in human psoriatic lesions. Our findings provide evidence that GPR109A is a target for the drug Fumaderm and suggest that niacin should be investigated to treat psoriasis in addition to its role in treating lipid disorders.
