METAP2 inhibitors and methods of treating obesity
Inventors
Petersen, John S. • Shanahan, James
Assignees
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Publication Number
US-9173956-B2
Publication Date
2015-11-03
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 disclosed methods cause weight loss in a subject in need thereof by administering a therapeutically effective amount of an active compound, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. The compounds encompass polymer-conjugated and peptide-linked methionine aminopeptidase-2 inhibitors, including fumagillin and fumagillol derivatives. These conjugates incorporate cleavable linkers, including self-immolating architectures that release carbamate derivatives, designed to deliver active moieties to target tissue and reduce efflux.
The defined Formula compounds comprise specified peptide and linker components associated with a methionine aminopeptidase-2 inhibitor moiety or alkyl, maintaining a molecular weight of less than about 60 kDa. Specific embodiments utilize polymer-fumagillol conjugates, such as HPMA-based conjugates with specified peptide sequences [procedural detail omitted for safety]. The conjugates provide weight-loss responses while improving metabolic parameters, including insulin, leptin, and glycemic measures, alongside enhanced stability and reduced neurotoxicity relative to unconjugated fumagillin derivatives.
Claims Coverage
The claims identify two independent claims directed to methods of causing weight loss in a subject through the administration of a therapeutically effective amount of active compounds, presenting two inventive features.
Administration of selected compounds to cause weight loss
The claim covers administering to a subject in need thereof a therapeutically effective amount of at least one compound selected from a specified group, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, to cause weight loss.
Administration of defined Formula compounds to cause weight loss
The claim covers administering a therapeutically effective amount of a compound of a defined Formula, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, to cause weight loss. The compound includes defined peptide and linker components coupled to a methionine aminopeptidase-2 inhibitor moiety or alkyl and has a molecular weight of less than about 60 kDa.
Together, the independent claims cover weight-loss methods using either compounds selected from a specified group or structurally defined peptide-linked Formula compounds having a molecular weight below approximately 60 kDa, including related pharmaceutical forms.
Stated Advantages
The conjugates are designed to release a modified active moiety in target tissue and reduce its efflux.
The claimed methods cause weight loss in a subject in need thereof, decreasing body fat and food consumption while substantially maintaining muscle mass.
The conjugates are intended to improve potency, water solubility, stability, serum half-life, and neurotoxicity relative to known fumagillin derivatives.
The conjugates are reported to produce greater weight reduction in diet-induced-obese models than unconjugated fumagillol or small-molecule comparators at lower exposure, allowing less frequent or lower-dose administration and providing an increased therapeutic index.
The methods demonstrate improvements in metabolic parameters, including insulin sensitivity, glycemic control, glucose tolerance, and leptin sensitivity.
Documented Applications
Methods for causing weight loss and treating obesity, metabolic syndrome, and related conditions in a subject in need thereof.
Improving insulin sensitivity, glycemic control, glucose tolerance, and leptin sensitivity.
Evaluations in diet-induced-obesity animal models.
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