Methods and formulations for modulating lyn kinase activity and treating related disorders
Inventors
Reaume, Andrew G. • Saporito, Michael S.
Assignees
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Publication Number
US-8835448-B2
Publication Date
2014-09-16
Expiration Date
Abstract
The present invention relates to compounds and pharmaceutically acceptable salts thereof and formulations comprising the compounds or a pharmaceutically acceptable salts thereof that are useful in modulating lyn kinase activity. In particular, the compounds or a pharmaceutically acceptable salts thereof are useful for treating or preventing a disease or disorder including cardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, metabolic syndrome (i.e., Syndrome X), a peroxisome proliferator activated receptor-associated disorder, septicemia, a thrombotic disorder, type II diabetes, obesity, pancreatitis, hypertension, renal disease, inflammation, or impotence.
Core Innovation
The patent describes Lyn kinasemodulating compounds of Formulas IVII, including example compound structures, pharmaceutically acceptable salts, and prodrugs. It states that these Lyn kinasemodulating compounds act as Lyn kinase activators/agonists and includes pharmaceutical compositions comprising the compounds, with therapeutically or prophylactically effective amounts and administration routes including oral administration.
The patent frames a problem in metabolic and related disorders, including metabolic syndrome (Syndrome X), type II diabetes, obesity, dyslipidemia/dyslipoproteinemia, cardiovascular and thrombotic diseases, inflammation, septicemia, renal disease, pancreatitis, hypertension, cancer, and impotence. It states that the compounds have insulin receptor pathway-like effects and are intended for prophylaxis and/or treatment of the listed disorders.
The patent provides illustrative results showing improvements associated with glucose tolerance and metabolic endpoints. It describes oral glucose tolerance improvements and reduced weight gain, fat pad weights, and leptin levels in illustrative diabetic/obesity models, and further describes increased in vitro Lyn kinase activity for illustrative compounds.
Claims Coverage
The claim set centers on a pharmaceutical composition combining a compound of a specified formula, or a pharmaceutically acceptable salt, with a selected therapeutic agent from listed drug classes. Dependent claims narrow the therapeutic-agent selection by specifying named members within those classes and refine at least one embodiment as a coated tablet dosage form.
Pharmaceutical composition with formula compound and selected therapeutic agent
A pharmaceutical composition comprising a compound of formula or a pharmaceutically acceptable salt thereof and a therapeutic agent chosen from metformin, insulin, a PPAR agonist, an insulin secretagogue, a sulfonylurea-based drug, and an -glucosidase inhibitor.
Pharmaceutical composition with specified PPAR agonist candidates
A pharmaceutical composition in which the PPAR agonist is selected from troglitazone, pioglitazone, rosiglitazone, ciglitazone, 5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione, AD 5075, WAY-120,744, englitazone, darglitazone, gemfibrozil, fenofibrate, clofibrate, and ciprofibrate.
Pharmaceutical composition with specified insulin secretagogue candidates
A pharmaceutical composition in which the insulin secretagogue is selected from forskolin, dibutryl cAMP, and isobutylmethylxanthine.
Pharmaceutical composition with specified sulfonylurea-based drug candidates
A pharmaceutical composition in which the sulfonylurea-based drug is selected from glisoxepid, glyburide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, phenbutamide, and tolcyclamide.
Pharmaceutical composition with listed therapeutic-agent classes together
A pharmaceutical composition in which the PPAR agonist, insulin secretagogue, sulfonylurea-based drug, and -glucosidase inhibitor are each selected from specified lists of named compounds.
Coated tablet pharmaceutical composition
A pharmaceutical composition formulated as a coated tablet.
Coverage centers on combining a compound of Formulas IVII, or a pharmaceutically acceptable salt, with an enumerated therapeutic agent class. Dependent claims narrow these choices by enumerating named candidates within the selected classes and refine at least one embodiment as a coated tablet.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Prophylaxis and/or treatment of disorders including metabolic syndrome (Syndrome X), type II diabetes, obesity, dyslipidemia/dyslipoproteinemia, cardiovascular and thrombotic diseases, inflammation, septicemia, renal disease, pancreatitis, hypertension, cancer, and impotence.
Oral administration use is described, with illustrative oral glucose tolerance improvements reported.
Use in illustrative diabetic/obesity models is described via reduced weight gain, fat pad weights, and leptin levels.
In vitro Lyn kinase activity increase is described for illustrative compounds.
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