Polymer-conjugated MetAP2 inhibitors, and therapeutic methods of use thereof
Inventors
Assignees
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Publication Number
US-10159692-B2
Publication Date
2018-12-25
Expiration Date
Abstract
One aspect of the invention provides polymer conjugated MetAP2 inhibitors. While not being bound by any particular theory, it is believed that coupling the MetAP2 inhibitory core via the linkers described herein provides compounds with superior efficacy to the parent small molecules and superior pharmacokinetic profiles. In one aspect of the invention, the polymer conjugated MetAP2 inhibitors are useful in methods of treating disease, comprising administering to a subject in need thereof a therapeutically effective amount of a polymer conjugated MetAP2 inhibitor.
Core Innovation
The disclosure concerns polymer-conjugated MetAP2 inhibitor compositions in which a MetAP2 inhibitor moiety, including MetAP2 inhibitory species such as fumagillin, is linked to a polymer backbone through variable linker elements and structural-variable substituents. The compositions define polymer parameters including x, y, and n, with ranges specified as x between 1 and about 450, y between 1 and about 30, and n between 1 and about 50.
The disclosed subject matter also provides compounds of the form Z-Q-X—Y—C(O)—W and polymer-conjugated therapeutic agents for use in pharmaceutical compositions. Z is defined as H2N-AA6-C(O) or H, the -Q-X—Y— portion is described as a self-immolating linker that releases a MetAP2 inhibitor as a carbamate derivative, and W is described as a MetAP2 inhibitor moiety.
The compositions include a polymer-conjugated compound together with a pharmaceutically acceptable carrier, and the document defines therapeutically effective amount and prophylactic and therapeutic treatment terminology. The disclosure also describes mammalian dosing guidance, combination therapy including combination with a chemotherapeutic agent and/or an anti-hypertensive agent, and a wide range of administration routes for the polymer-conjugated therapeutic agents.
Claims Coverage
The provided claim set includes two independent claims that each recite a pharmaceutical composition comprising the specified compound together with a pharmaceutically acceptable carrier. Across the independent claims, the inventive features are the specified compound in the composition and, for one claim, quantitative limits on x, y, and n.
Pharmaceutical composition with carrier and parameter ranges (x, y, n)
A pharmaceutical composition comprising the compound in which x is between 1 and about 450, y is between 1 and about 30, and n is between 1 and about 50, together with a pharmaceutically acceptable carrier.
Pharmaceutical composition with carrier
A pharmaceutical composition comprising the compound together with a pharmaceutically acceptable carrier.
The claims cover pharmaceutical compositions that include the disclosed Z-Q-X—Y—C(O)—W compound, described as including a MetAP2 inhibitor moiety W and a self-immolating linker, combined with a pharmaceutically acceptable carrier. One independent claim further restricts the compound to specific parameter ranges for x, y, and n.
Stated Advantages
Lower required doses and increased activity per weight compared to small molecules.
Documented Applications
Treating disease by administering an effective amount of the polymer conjugated MetAP2 inhibitor composition to a mammal.
Mammalian administration of polymer-conjugated therapeutic agents.
Combination therapy including combination with a chemotherapeutic agent and/or an anti-hypertensive agent.
Use across multiple administration routes listed for administration of the polymer-conjugated therapeutic agents.
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