ABSTRACT
Bile acid signaling and metabolism in the gastrointestinal tract have wide-ranging influences on systemic disease. G protein-coupled bile acid receptor 1 (GPBAR1, TGR5) is one of the major effectors in bile acid sensing, with demonstrated influence on metabolic, inflammatory, and proliferative processes. The pharmacologic utility of TGR5 agonists has been limited by systemic target-related effects such as excessive gallbladder filling and blockade of gallbladder emptying. Gut-restricted TGR5 agonists, however, have the potential to avoid these side effects and consequently be developed into drugs with acceptable safety profiles. We describe the discovery and optimization of a series of gut-restricted TGR5 agonists that elicit a potent response in mice, with minimal gallbladder-related effects. The series includes 12 (TGR5 EC50: human, 143 nM; mouse, 1.2 nM), a compound with minimal systemic availability that may have therapeutic value to patients with type 2 diabetes mellitus, nonalcoholic steatohepatitis, or inflammatory bowel disease.
Subject(s)
Gallbladder/drug effects , Gastrointestinal Agents/pharmacology , Receptors, G-Protein-Coupled/agonists , Thiazolidines/chemistry , Animals , Dogs , Drug Design , Drug Evaluation, Preclinical/methods , Female , Gastrointestinal Agents/adverse effects , Gastrointestinal Agents/chemistry , Glucagon-Like Peptide 1/metabolism , HEK293 Cells , Humans , Madin Darby Canine Kidney Cells , Male , Mice, Inbred C57BL , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in patients with CKD, and (3) reduce interdialytic weight gain and intradialytic hypotension in ESRD. Here, we report the effects of tenapanor on dietary phosphorous absorption. Oral administration of tenapanor or other intestinal sodium-hydrogen exchanger 3 inhibitors increased fecal phosphorus, decreased urine phosphorus excretion, and reduced [(33)P]orthophosphate uptake in rats. In a rat model of CKD and vascular calcification, tenapanor reduced sodium and phosphorus absorption and significantly decreased ectopic calcification, serum creatinine and serum phosphorus levels, circulating phosphaturic hormone fibroblast growth factor-23 levels, and heart mass. These results indicate that tenapanor is an effective inhibitor of dietary phosphorus absorption and suggest a new approach to phosphate management in renal disease and associated mineral disorders.
Subject(s)
Calcinosis/prevention & control , Gastrointestinal Tract/drug effects , Isoquinolines/therapeutic use , Phosphorus/urine , Renal Insufficiency, Chronic/drug therapy , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sulfonamides/therapeutic use , Animals , Calcinosis/etiology , Disease Models, Animal , Gastrointestinal Tract/metabolism , Isoquinolines/pharmacology , Male , Random Allocation , Rats, Sprague-Dawley , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/metabolism , Sodium/metabolism , Sodium-Hydrogen Exchanger 3 , Sodium-Hydrogen Exchangers/metabolism , Sulfonamides/pharmacologyABSTRACT
Cortisol is an important glucocorticoid that regulates many physiological pathways by activating various intracellular receptors. The type 1 isozyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) functions in vivo predominantly as a reductase by converting cortisone into cortisol. A high-throughput liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed to screen for inhibitors of 11beta-HSD1 by monitoring cortisol and cortisone simultaneously. The injection cycle time can be as fast as 1 min/sample, making it amenable to the analysis of large numbers of the cell-assay samples in the screening of 11beta-HSD inhibitors. The reductase and dehydrogenase activities of 11beta-HSD1 are assessed separately.