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
The management of sodium intake is clinically important in many disease states including heart failure, kidney disease, and hypertension. Tenapanor is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney. When administered orally to rats, tenapanor acted exclusively in the gastrointestinal tract to inhibit sodium uptake. We showed that the systemic availability of tenapanor was negligible through plasma pharmacokinetic studies, as well as autoradiography and mass balance studies performed with (14)C-tenapanor. In humans, tenapanor reduced urinary sodium excretion by 20 to 50 mmol/day and led to an increase of similar magnitude in stool sodium. In salt-fed nephrectomized rats exhibiting hypervolemia, cardiac hypertrophy, and arterial stiffening, tenapanor reduced extracellular fluid volume, left ventricular hypertrophy, albuminuria, and blood pressure in a dose-dependent fashion. We observed these effects whether tenapanor was administered prophylactically or after disease was established. In addition, the combination of tenapanor and the blood pressure medication enalapril improved cardiac diastolic dysfunction and arterial pulse wave velocity relative to enalapril monotherapy in this animal model. Tenapanor prevented increases in glomerular area and urinary KIM-1, a marker of renal injury. The results suggest that therapeutic alteration of sodium transport in the gastrointestinal tract instead of the kidney--the target of current drugs--could lead to improved sodium management in renal disease.
Subject(s)
Intestinal Mucosa/metabolism , Kidney/pathology , Myocardium/pathology , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sodium/metabolism , Albuminuria/complications , Albuminuria/drug therapy , Albuminuria/physiopathology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Blood Pressure/drug effects , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Electrolytes/urine , Enalapril/pharmacology , Enalapril/therapeutic use , Feces , Healthy Volunteers , Humans , Hypertrophy , Intestines/drug effects , Isoquinolines/administration & dosage , Isoquinolines/pharmacokinetics , Isoquinolines/pharmacology , Isoquinolines/therapeutic use , Kidney/drug effects , Kidney/metabolism , Male , Myocardium/metabolism , Nephrectomy , Rats , Rats, Sprague-Dawley , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/physiopathology , Sodium Chloride, Dietary/administration & dosage , Sodium Chloride, Dietary/pharmacology , Sodium-Hydrogen Exchanger 3 , Sodium-Hydrogen Exchangers/metabolism , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Sulfonamides/therapeutic useABSTRACT
Optimization of a tri-substituted N-pyridyl amide led to the discovery of a new class of potent N-pyrimidyl amide based p38alpha MAP kinase inhibitors. Initial SAR studies led to the identification of 5-dihydrofuran as an optimal hydrophobic group. Additional side chain modifications resulted in the introduction of hydrogen bond interactions. Through extensive SAR studies, analogs bearing free amino groups and alternatives to the parent (S)-alpha-methyl benzyl moiety were identified. These compounds exhibited improved cellular activities and maintained balance between p38alpha and CYP3A4 inhibition.
Subject(s)
Amides/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Amides/chemistry , Drug Design , Models, Molecular , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38alpha MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene.
Subject(s)
Drug Design , Indoles/chemical synthesis , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Piperazines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Animals , Dogs , Haplorhini , Humans , Indoles/pharmacokinetics , Mitogen-Activated Protein Kinase 14/metabolism , Piperazine , Piperazines/pharmacokinetics , Protein Binding/drug effects , Protein Binding/physiology , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Secondary , RatsABSTRACT
The design and synthesis of a new class of p38alpha MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38alpha enzymatic and cell-based cytokine TNFalpha production inhibition assays. The optimal linkers between the piperidine and the oxalyl amide were found to be [6,5] fused ring heterocycles. Substituted indoles and azaindoles were favored structural motifs in the cellular assay.