METAP2 inhibitors and methods of treating obesity
Inventors
Petersen, John S. • Shanahan, James
Assignees
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Publication Number
US-10588904-B2
Publication Date
2020-03-17
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 relates to a method for lowering or decreasing blood glucose levels in a subject in need thereof by administering at least one compound, or a pharmaceutically acceptable salt thereof, of a specified Formula in a therapeutically effective amount. The compound includes a defined linker or variable segment Z expressed as —NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X-Y—C(O)—W, with independently defined groups R4, R5, and R6.
The Formula defines AA1 through AA6 as selected from bonds and listed amino-acid residues, with AA1 limited to glycine, alanine, or H2N(CH2)mCO2H and AA6 optionally being H2N(CH2)mCO2H. Q, X, Y, M, J, and V are defined by allowed heteroatom and structural options, and X includes the stated M-(C(R)2)p-M-J-M-(C(R)2)p-M-V pattern. The structural definition positions a methionine aminopeptidase-2 inhibitor moiety W within the conjugate architecture.
The disclosed compounds are described as drug conjugate or polymer-conjugated MetAP2 inhibitors intended for treating obesity and metabolic syndrome-related conditions, with a focus on lowering or decreasing blood glucose levels. The document further states that a cleavable linker provides release of a modified active moiety, with low or no cleavage in plasma and preferential cleavage in disease tissue, and links the design to improved pharmacokinetics, efficacy, and reduced efflux from target tissues/cells.
Claims Coverage
Two independent claim themes are present: administration of a selected compound to lower or decrease blood glucose levels, and administration of a Formula-defined compound containing a methionine aminopeptidase-2 inhibitor moiety (W) in a therapeutically effective amount. Across the consolidated claims, the inventive coverage centers on one blood-glucose-lowering method framework with defined conjugate architecture and structural variable constraints.
Blood glucose lowering by administration of selected compound
A method for lowering or decreasing blood glucose levels in a subject in need thereof by administering at least one compound, or a pharmaceutically acceptable salt thereof, selected from the group, in a therapeutically effective amount.
Formula-defined conjugate with methionine aminopeptidase-2 inhibitor moiety
A method for lowering or decreasing blood glucose levels in a subject by administering at least one compound, or a pharmaceutically acceptable salt thereof, of the Formula, wherein R4 is H or C1-C6 alkyl, R5 is H or C1-C6 alkyl, R6 is C2-C6 hydroxyalkyl, Z is —NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X-Y—C(O)—W, Q is NR, O, or S, X is M-(C(R)2)p-M-J-M-(C(R)2)p-M-V, Y is NR, O, or S, and W is a methionine aminopeptidase-2 inhibitor moiety, administered in a therapeutically effective amount.
The consolidated claim coverage is directed to lowering or decreasing blood glucose levels by administering therapeutically effective amounts of compounds that are either selected from the stated group or defined by a Formula incorporating the Z linker, Q-X-Y substructure, and methionine aminopeptidase-2 inhibitor moiety W.
Stated Advantages
Improved pharmacokinetics.
Improved efficacy.
Reduced efflux from target tissues/cells.
Lowers or decreases blood glucose levels in a subject.
Improved insulin sensitivity is supported by reported HOMA-IR calculations and reduced insulin readouts in the described in vivo context.
Documented Applications
Treating obesity and metabolic syndrome using drug conjugates/polymer conjugates of MetAP2 inhibitors to lower or decrease blood glucose levels in a subject in need thereof.
Using the described method to lower or decrease blood glucose levels in a subject in need thereof.
In vivo metabolic efficacy evaluation in diet-induced obese (DIO) male Levin rats and male C57Bl/6 mice treated with Compound 16 and related agents, using OGTT/ipGTT-related blood glucose measurements, weight-change data, HOMA-IR insulin sensitivity, food consumption, and leptin measurements.
Schedule comparison of dosing regimens in mice, including q4d vs q8d and CKD-732 q2d vs q4d, together with body-weight time-course comparisons for several compound analogs and polymer controls.
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