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-11033548-B2
Publication Date
2021-06-15
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 invention is directed to Lyn-kinase modulators provided as compositions and administered as therapeutics. The described pharmaceutical compositions comprise a compound of formula and/or a pharmaceutically acceptable salt, with the treatment focused on mammalian insulin resistance or prediabetes.
The problem being solved is insulin resistance and prediabetes, which are addressed by administering an effective amount of a Lyn-kinase modulating compound composition. Lyn activation/upregulation is presented as being associated with insulin receptor pathway activity, thereby linking Lyn kinase modulation to improvement in insulin-related metabolic dysregulation.
The document further ties the therapeutic concept to Lyn-kinase-associated disorders and metabolic disease states, including metabolic syndrome and type II diabetes, obesity, cardiovascular disease, dyslipidemia/dyslipoproteinemia, inflammation, septicemia, thrombotic disorders, renal disease, and impotence.
Claims Coverage
The independent claim is directed to treating insulin resistance or prediabetes by administering a defined formula compound or pharmaceutically acceptable salt. The claim set further includes specific substituent constraints, route-dependent dosing ranges, and concurrent administration with selected therapeutic agent classes.
Treating insulin resistance or prediabetes by Lyn-kinase modulator composition
A method of treating insulin resistance or prediabetes in a mammal comprising administering to the mammal in need thereof an effective amount of a composition comprising a compound of formula or a pharmaceutically acceptable salt thereof.
Specific compound substituent constraints
The compound of formula is defined wherein R1 is methyl and n is 1, X is a halogen, and m is 0 or 1.
Oral dosing range for the compound
Administering the composition comprising the compound orally at a dosage of 0.5 mg to 20 mg per kilogram of body weight or 1 mg to 10 mg per kilogram of body weight.
Intravenous dosing range for the compound
Administering the composition comprising the compound intravenously at a dosage of 0.1 mg to 35 mg per kilogram of body weight or 1 mg to 10 mg per kilogram of body weight.
Intranasal dosing range for the compound
Administering the composition comprising the compound intranasally at a dosage ranging from 0.01 pg to 1 mg per kilogram of body weight.
Concurrent combination with selected therapeutic agent classes
Administering the composition comprising the compound concurrently with administration of another therapeutic agent selected from a statin, a PPAR agonist, a bile-acid-binding resin, niacin, a RXR agonist, an anti-obesity drug, a hormone, an insulin secretagogue, a tyrophostine, a sulfonylurea-based drug, metformin, an α-glucosidase inhibitor, an apo A-I agonist, apolipoprotein E, a cardiovascular drug, and a chemotherapeutic agent.
Concurrent combination with named active agents within listed categories
The concurrent therapeutic agent is selected from particular active agents within the statin, PPAR agonist, bile-acid-binding resin, RXR agonist, anti-obesity drug, hormone, insulin secretagogue, tyrophostine, sulfonylurea-based drug, α-glucosidase inhibitor, apo A-I agonist, cardiovascular drug, and chemotherapeutic agent lists.
Claim coverage centers on administering an effective amount of a defined formula Lyn-kinase modulator or salt to treat insulin resistance or prediabetes, with further coverage for specific substituent constraints and route-dependent dosing. Additional coverage includes concurrent administration with other listed therapeutic classes and specific named active agents.
Stated Advantages
Improved oral glucose tolerance in diabetes/obesity contexts as described.
Reduced blood glucose in mouse and rat models as described.
Reduced weight gain and fat pad development without affecting food intake as described.
Altered leptin levels as described.
Increased Lyn kinase enzyme activity for certain compounds as described.
Documented Applications
Treatment or prevention of insulin resistance or prediabetes in a mammal by administering an effective amount of a composition comprising a compound of formula or a pharmaceutically acceptable salt.
Therapeutic use for Lyn-kinase-associated disorders including metabolic syndrome, type II diabetes, obesity, cardiovascular disease, dyslipidemia/dyslipoproteinemia, inflammation, septicemia, thrombotic disorders, renal disease, and impotence as described in the document summary context.
Diabetes/obesity model functional contexts described, including oral glucose tolerance improvements, reduced blood glucose, reduced weight gain and fat pad development, changes in leptin, and increased Lyn kinase activity as described in examples.
Combination therapy contexts described involving concurrent administration with other therapeutic agents selected from statins, PPAR agonists, bile-acid-binding resins, niacin, RXR agonists, anti-obesity drugs, hormones/insulin-related agents, sulfonylureas, metformin, α-glucosidase inhibitors, apoA-I/apoE-related agents, cardiovascular drugs, and chemotherapeutics as described.
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