ABSTRACT
The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.
Subject(s)
Benzhydryl Compounds/pharmacology , Hypoglycemic Agents/pharmacology , Phenylbutyrates/pharmacology , Sodium-Glucose Transporter 1/antagonists & inhibitors , Thioglycosides/pharmacology , Animals , Benzhydryl Compounds/administration & dosage , Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/chemistry , Glucose/metabolism , Glucose Tolerance Test , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Intestinal Absorption/drug effects , Male , Mice, Knockout , Phenylbutyrates/administration & dosage , Phenylbutyrates/chemical synthesis , Phenylbutyrates/chemistry , Structure-Activity Relationship , Thioglycosides/administration & dosage , Thioglycosides/chemical synthesis , Thioglycosides/chemistryABSTRACT
The rat has been the preferred rodent toxicology species since before regulatory requirements have been in place, and there exists in the pharmaceutical industry and the regulatory agencies a significant amount of historical data for the rat. The resulting experience base with the rat makes the possibility of replacing it with the mouse for regulated toxicology studies untenable for all but the most extreme circumstances. However, toxicologists are very familiar with the mouse as a model for chronic carcinogenicity studies, and there exist multiple preclinical mouse models of disease. The authors evaluated the use of the mouse for early in vivo toxicology signal generation and prioritization of small molecule lead compounds prior to nomination of a development candidate. In five-day oral gavage studies with three test agents in the mouse, the authors were able to identify the same dose-limiting toxicities as those identified in the rat, including examples of compound-mediated hemolysis as well as microscopic lesions in the alimentary canal, kidney, and pancreas. Performing early signal generation studies in the mouse allows for earlier assessment of the safety liabilities of small molecules, requires significantly less compound, and allows evaluation of more compounds earlier in the project's life cycle.
Subject(s)
Disease Models, Animal , Mice , Toxicity Tests/methods , Animals , Antineoplastic Agents/toxicity , Enzyme Inhibitors/toxicity , Male , Mice, Inbred C57BL , Rats , Rats, Sprague-DawleyABSTRACT
During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.
