Inhibitors of diacylglycerol O-acyltransferase 1 (DGAT-1) and uses thereof
Inventors
Reddy, K. Raja • Stebbins, Jeff • Boyer, Serge H. • Erion, Mark D. • Hecker, Scott J. • Raffaele, Nicholas Brian • Bookser, Brett C. • Mali, Venkat Reddy
Assignees
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Publication Number
US-9340566-B2
Publication Date
2016-05-17
Expiration Date
Abstract
The invention pertains to the use of fused bicyclo heterocyclic adducts of thiohydroxy pyridines or pyrimidines as diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors to treat hyperlipidiemias and various diseases and disorders associated therewith. Other conditions also can be ameliorated or avoided, such as high postprandial triglycerides or diet-related hypertriglyceridemia, cardiovascular risk associated with excessive triglycerides, and insulin resistance/glucose intolerance in overweight patients, those with diabetes or other glucose metabolic disorders such as Syndrome X and/or polycystic ovary disease.
Core Innovation
The invention relates to administering DGAT-1 inhibitor agents to a mammal for treating and/or preventing diseases or conditions selected from Type 2 diabetes, insulin resistance syndrome, obesity, impaired glucose tolerance, hyperglycemia, high postprandial triglycerides, diet- or obesity-related hypertriglyceridemia, cardiovascular risk associated with excessive triglycerides, insulin resistance or glucose intolerance. The DGAT-1 inhibitor agents are compounds of Formula (I) and include pharmaceutically acceptable salts, stereoisomers, and pharmaceutical compositions.
The compounds of Formula (I) are described within a defined structural scope including the Q-G1-G2-G3-G4-Z framework, fused bicyclic heteroaryl structures, variable substituents, and additional provisos restricting certain combinations. The disclosure provides definitions, example-related tables, and synthesized compounds, including elemental analysis and mass spectrometry information associated with the listed compounds.
The described approach targets enterocytes to lower systemic exposure and reduce systemic side effects while inhibiting DGAT-1. The document includes oral administration and other pharmaceutical compositions, as well as biological evaluation using DGAT-1 IC50 classifications and rodent outcome summaries.
Claims Coverage
The identified independent claim is a treatment method using Formula (I) DGAT-1 inhibitor compounds. It covers administration of therapeutically effective amounts of the defined compounds, including salts, stereoisomers, or pharmaceutical compositions, for specified metabolic and triglyceride-associated conditions, optionally with anti-diabetic and/or anti-obesity agents.
Enteric DGAT-1 inhibitor compound treatment for metabolic and triglyceride-associated diseases
A method of treating a disease or condition in a mammal by administering a therapeutically effective amount of a compound of Formula (I), including a pharmaceutically acceptable salt, a stereoisomer, or a pharmaceutical composition, where the disease or condition is selected from Type 2 diabetes, insulin resistance syndrome, obesity, impaired glucose tolerance, hyperglycemia, high postprandial triglycerides, diet- or obesity-related hypertriglyceridemia, cardiovascular risk associated with excessive triglycerides, insulin resistance or glucose intolerance.
Administration with optional anti-diabetic and/or anti-obesity agent combination
The method further comprises administering the Formula (I) compound either alone or in combination with an anti-diabetic agent and/or an anti-obesity agent.
Formula (I) structural scope with Q-G1-G2-G3-G4-Z framework
In Formula (I), Q, G1, G2, G3, G4, and Z are defined by specified selections and substituent groups, including fused bicyclic heteroaryl structures and additional provisos restricting certain combinations.
Overall, the claim coverage centers on administering therapeutically effective Formula (I) DGAT-1 inhibitor compounds to treat specified metabolic and triglyceride-related diseases, optionally in combination with anti-diabetic and/or anti-obesity agents, with the compound scope defined by the Q-G1-G2-G3-G4-Z framework.
Stated Advantages
Selectively targeting enterocytes to lower systemic exposure and reduce systemic side effects.
Documented Applications
Treating and/or preventing Type 2 diabetes, insulin resistance syndrome, obesity, impaired glucose tolerance, hyperglycemia, high postprandial triglycerides, diet- or obesity-related hypertriglyceridemia, including cardiovascular risk associated with excessive triglycerides, insulin resistance or glucose intolerance.
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