METAP2 inhibitors and methods of treating obesity
Inventors
Petersen, John S. • Shanahan, James
Assignees
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Publication Number
US-10010544-B2
Publication Date
2018-07-03
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 invention relates to methods for improving glycemic control in a subject in need thereof by administering at least one compound, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount. The compounds are defined by a chemical Formula having multiple independently selected substituent definitions, including R4, R5, R6, Z, AA1 through AA6, L, Q, X, M, J, Y, V, R, R10 through W, and by inclusion of a methionine aminopeptidase-2 inhibitor moiety as W.
The structural definition of Z is expressed as —NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X—Y—C(O)—W. AA1 is glycine, alanine, or H2N(CH2)mCO2H, and AA2 through AA6 include bonds or specified amino-acid selections, with AA5 and AA6 further restricted to particular subsets in some embodiments. Q is NR, O, or S; X, M, J, and Y are structural fragments with defined connectivity patterns; and W is a methionine aminopeptidase-2 inhibitor moiety according to the recited structure and parameter ranges.
The disclosed embodiments include specific compound structures by defining Z using combinations of amino-acid identities for AA3 through AA6 and an illustrated Q-X—Y linker group, together with alternative W moieties. The description references polymer-linked therapeutic conjugate compounds, cleavable or self-immolating linker architecture, and target/disease tissue cleavage to yield a modified active moiety with reduced efflux and improved pharmacokinetic and efficacy.
Claims Coverage
The independent claims cover methods for improving glycemic control by administering a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof. The inventive coverage is driven by the administration framework and by the defined Formula including the Z backbone and the methionine aminopeptidase-2 inhibitor moiety W.
Improving glycemic control by administering a therapeutically effective amount
A method for improving glycemic control in a subject in need thereof comprising administering at least one compound, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the subject.
Defined formula with a methionine aminopeptidase-2 inhibitor moiety
A method for improving glycemic control in a subject in need thereof comprising administering at least one compound, or a pharmaceutically acceptable salt thereof, of the Formula, wherein Z is —NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X—Y—C(O)—W and W is a methionine aminopeptidase-2 inhibitor moiety according to the recited structure.
Constrained amino-acid identity selection for AA1 through AA6
AA1 is glycine, alanine, or H2N(CH2)mCO2H; AA2 through AA6 are selected from bonds or specified amino acids, with AA5 and AA6 further limited to particular subsets in some claims.
Defined moiety connectivity for Q, X, J, Y, and V
Q is NR, O, or S; X is M-(C(R)2)p-M-J-M-(C(R)2)p-M-V; M is a bond or C(O); J is a bond or selected ring or heteroatom-containing groups; Y is NR, O, or S; and V is a bond or a defined substituent arrangement, with W as the terminal methionine aminopeptidase-2 inhibitor moiety.
Cleavable-linker MetAP2 inhibitor conjugate
A method for improving glycemic control comprising administering a compound selected from the described conjugates, where the conjugate includes an active MetAP2 inhibitor moiety linked through a cleavable or self-immolating linker that is preferentially cleaved in target/disease tissue to yield a modified active moiety.
Claim coverage is centered on improving glycemic control by administering compounds or salts in a therapeutically effective amount, and on compounds defined by a broad structural Formula with constrained amino-acid selections, defined connectivity, and a terminal methionine aminopeptidase-2 inhibitor moiety.
Stated Advantages
Improving glycemic control in a subject in need thereof.
Reduced efflux of the modified active moiety.
Improved pharmacokinetic.
Improved efficacy.
Documented Applications
Method for improving glycemic control in a subject in need thereof.
Methods of improving glycemic control in a subject in need thereof by administering polymer-linked therapeutic conjugate compounds or pharmaceutically acceptable salts as defined.
Administering compounds described as anti-obesity/MetAP2 inhibitors including fumagillin, fumagillol, and analogs.
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