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-11304944-B2
Publication Date
2022-04-19
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 invention provides compounds and pharmaceutically acceptable salts defined by a structural Formula for reducing insulin levels in a subject in need thereof by administering at least one compound in a therapeutically effective amount. The Formula includes variable substituents R4, R5, and R6, a defined Z moiety incorporating AA1 through AA6, and a methionine aminopeptidase-2 inhibitor moiety W. The structural framework includes Z as an NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-W motif and allowed selections for Q, X, and Y.
In the described embodiments, AA1 is glycine, alanine, or H2N(CH2)mCO2H with m selected as 2, 3, 4 or 5, while AA2 through AA6 are each constrained to a bond or specified amino acids. Q and Y are each selected from NR, O, or S, and X is defined by the M-(C(R)2)p-M-J-M-(C(R)2)p-M-V framework with variable linker options. The document also states that Q-X-Y functions as a self-immolating linker releasing the MetAP2 inhibitor as a carbamate derivative.
The invention further relates to methionine aminopeptidase-2 inhibitor-based polymer conjugates and modified active moieties, including fumagillin and fumagillol derivatives and polymer conjugate variants. The disclosed compounds are associated with treatment of obesity and metabolic syndrome, and the text states that the compounds are intended to be more potent and to have reduced toxicity, improved solubility, and longer half-life.
Claims Coverage
The consolidated claim coverage includes independent claims directed to methods for reducing insulin levels by administering compounds defined by structural Formulae. Across the claims, the core inventive features center on the Z-linked AA1-AA6 architecture, the Q/X/Y linker and heteroatom framework, and inclusion of a methionine aminopeptidase-2 inhibitor moiety W. The provided claim set repeatedly ties these structural constraints to therapeutically effective administration.
Reducing insulin levels by administering Formula compounds
A method for reducing insulin levels in a subject in need thereof comprising administering at least one compound, or a pharmaceutically acceptable salt thereof, of the Formula in a therapeutically effective amount.
Z as an NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-W motif
Z is defined as —NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-W, with AA1 through AA6 selected from the enumerated bond and amino acid options and linked to Q, X, Y, and W.
Defined heteroatom and linker selections for Q, X, and Y
Q and Y are each NR, O, or S, and X is defined by the M-(C(R)2)p-M-J-M-(C(R)2)p-M-V framework with specified bond and structural options for M, J, and V.
Methionine aminopeptidase-2 inhibitor moiety W
W is a methionine aminopeptidase-2 inhibitor moiety, with the Formula further defining variable ranges for x, y, n, p, q, and r where provided.
Polymer conjugate and modified active moiety embodiments
The claims also cover methionine aminopeptidase-2 inhibitor-based polymer conjugates and selected compounds used in insulin-reducing methods.
The claim coverage is directed to insulin-lowering methods implemented by administering structurally defined compounds. The recurring inventive features are the AA1-AA6 based Z segment, the Q/X/Y linker architecture, and the explicit inclusion of a methionine aminopeptidase-2 inhibitor moiety W, with polymer conjugate and selected-compound embodiments also present.
Stated Advantages
More potent compounds
Reduced toxicity
Improved solubility
Longer half-life
Preferential cleavage in target tissue to reduce active-moiety efflux.
Reducing insulin levels in a subject in need thereof.
Greater and schedule-dependent weight loss compared with Compound 1 and CKD-732 on comparable schedules.
Larger insulin reductions and insulin sensitivity improvements compared with Compound 1 and CKD-732 on comparable schedules.
Polymer lacking fumagillol is described as showing vehicle-like effects.
Greater efficacy of the fumagillol polymer conjugate relative to the referenced comparators in reported in vivo evaluations.
Reduced fumagillol exposure for the polymer conjugate while maintaining the greater efficacy reported in the document.
Preference for a large therapeutic index.
Dose-ranging and dose determination linked to toxicity/efficacy metrics and exposure metrics.
Documented Applications
Treatment of obesity and metabolic syndrome, including improving insulin sensitivity and glycemic control and reducing insulin levels.
Reducing insulin levels in a subject in need thereof.
A method for reducing insulin levels in a subject in need thereof.
In vivo diet-induced obesity (DIO) rat and DIO mouse studies comparing Compound 16, TNP-470/Compound 1, and CKD-732, with reported effects on insulin levels, glucose tolerance/HOMA-IR, body weight, lipids, and liver enzymes.
Assessment of schedule-dependent metabolic outcomes, including fasting insulin, OGTT glucose/insulin sensitivity via HOMA-IR, leptin, and body-weight outcomes under different dosing schedules and compound variants.
Obesity-related treatment outcomes, including goals such as risk reduction, weight reduction, food intake, metabolic rate, and quality of life.
Interested in licensing this patent?