MetAP2 inhibitors and methods of treating obesity
Inventors
Petersen, John S. • Shanahan, James
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9757373-B2
Publication Date
2017-09-12
Expiration Date
Abstract
The present invention relates to modified or polymer conjugated MetAP2 inhibitors. The present invention also relates to methods of preventing, inducing, causing or increasing weight loss, treating obesity and/or treating metabolic syndrome utilizing the modified or polymer conjugated MetAP2 inhibitors. The present invention also relates to methods of improving insulin sensitivity and glycemic control, reducing insulin levels and/or improving leptin sensitivity utilizing the modified or polymer conjugated MetAP2 inhibitors.
Core Innovation
The disclosure relates to methods for causing weight loss in a subject in need thereof by administering polymer-conjugated methionine aminopeptidase-2 inhibitors, including fumagillin and fumagillol conjugates, or pharmaceutically acceptable salts thereof. These conjugates link inhibitor moieties through peptide-containing and aminoalkyl linkers to HPMA-based polymers, including specified oligopeptide variants. Cleavable linkers release modified active moieties designed with reduced target tissue efflux to improve tissue delivery, duration of activity, and pharmacokinetic properties.
The polymer conjugates provide dose-responsive body-weight reduction, fat loss, and decreased food intake in diet-induced obesity models, outperforming unconjugated fumagillol compounds. Conjugation improves water solubility, stability, potency, and serum half-life while reducing systemic exposure and neurotoxicity. Documented treatment outcomes include improvements in glycemic control, glucose tolerance, insulin sensitivity, lipid profiles, and leptin measures.
Claims Coverage
The independent claims provide two inventive features directed to methods for causing weight loss in a subject in need thereof.
Administration of selected compounds to cause weight loss
An independent claim covers administering to a subject in need thereof a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, selected from a recited group to cause weight loss.
Administration of formula-defined compounds to cause weight loss
An independent claim covers administering a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, of a specified Formula defining variable substituents, peptide-containing linkers, and a methionine aminopeptidase-2 inhibitor moiety or alkyl to cause weight loss.
The independent claims recite methods for causing weight loss through the administration of compounds selected from a defined group or compounds encompassed by a specified Formula incorporating peptide, linker, and inhibitor components.
Stated Advantages
Polymer conjugates provide greater weight reduction and fat loss in diet-induced obesity models than unconjugated fumagillol compounds, with effects varying by dose and dosing interval.
The polymer conjugates are associated with lower molar doses, less frequent administration, reduced systemic exposure, and an improved therapeutic index compared with unconjugated compounds.
The cleavable-linker design releases modified active moieties with reduced efflux from target tissue, improving tissue delivery, duration of activity, and pharmacokinetic properties.
Treatment results in reduced food intake and food consumption.
The disclosed conjugates improve insulin sensitivity, glycemic control, glucose tolerance, HOMA-IR, lipid measures, and leptin sensitivity while reducing insulin levels.
Conjugation improves water solubility, stability, potency, and serum half-life while reducing neurotoxicity.
Documented Applications
Causing or inducing weight loss in a subject in need thereof by administering a recited compound, Formula-defined conjugate, or pharmaceutically acceptable salt thereof.
Treating or ameliorating obesity, obesity-related conditions, and associated co-morbidities.
Treating metabolic disorders, including metabolic syndrome.
Interested in licensing this patent?