Chemical conjugates of Evans Blue derivatives and their use in the production of long-acting therapeutics
Inventors
Chen, Xiaoyuan • Lang, Lixin • Niu, Gang
Assignees
US Department of Health and Human Services
Publication Number
US-10709790-B2
Publication Date
2020-07-14
Expiration Date
2036-06-21
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present invention is directed to a compound of Formula I or Formula II or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of such an ester or amide or a solvate of such an ester amide or salt: Formula I Formula II The compounds of Formula I may be covalently bonded to a therapeutic compound or fragment thereof to provide a compound of Formula II and thereby extend the half-life of the therapeutic compound. The invention is also directed to pharmaceutical compositions of the disclosed compounds, as well as their use in the diagnosis or treatment of diseases.
Core Innovation
The invention provides chemical conjugates of Evans Blue dye derivatives, specifically compounds of Formula I and Formula II, or pharmaceutically acceptable esters, amides, solvates, or salts thereof. Compounds of Formula I can be covalently bonded to therapeutic compounds or fragments thereof to form compounds of Formula II, thereby extending the half-life of the therapeutic compound. Pharmaceutical compositions comprising these compounds are also disclosed, along with their use in the diagnosis or treatment of diseases such as diabetes and cancer.
The problem addressed by the invention is the need to improve the pharmacokinetics, specifically the half-life, of pharmaceutical compounds. Protein drugs are especially vulnerable to rapid degradation and clearance, such as renal filtration, which limits their effectiveness. Existing methods to increase half-life, such as PEGylation, lipidation, or fusion with larger proteins like albumin or Fc domains, have drawbacks including compromised biological activity, non-optimal biodistribution, and increased complexity in chemical synthesis.
Because human serum albumin (HSA) is the most abundant blood plasma protein and has a long half-life via interaction with the neonatal Fc receptor (FcRn), albumin-based drug delivery has been exploited to improve drug half-life. Evans Blue dye binds strongly to serum albumin and has been used for blood volume measurements and imaging. The invention leverages functionalized Evans Blue derivatives covalently conjugated to therapeutic compounds to harness albumin binding for extending the in vivo half-life of drugs with improved pharmacokinetics and biodistribution, offering a versatile platform for long-acting therapeutics.
Claims Coverage
The patent includes 3 independent claims focusing on chemical compounds of Formula I, compounds of Formula II conjugated with therapeutic compounds, and pharmaceutical compositions containing compounds of Formula II.
Compounds of Formula I
A class of Evans Blue derivative compounds characterized by variable substituents R1-R11 chosen independently from hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl, alkoxy, haloalkyl, and haloalkoxy, and a linking group L1 defined as a polymethylene chain optionally substituted or modified with oxygen or amide groups, enabling chemical modification and potential radionuclide labeling.
Compounds of Formula II comprising a therapeutic compound conjugate
Compounds where the Evans Blue derivative (Formula I) is covalently linked to a therapeutic compound or its fragment (R), allowing extension of the therapeutic's half-life. The linking groups L1 and L2 provide attachment points with defined chemical characteristics to retain function, and the therapeutic moiety may include peptides, proteins, or small molecules such as insulin, Exendin-4, and anti-cancer drugs.
Pharmaceutical compositions including compounds of Formula II
Pharmaceutical compositions comprising the compound of Formula II along with pharmaceutically acceptable carriers, enabling formulation into various dosage forms suitable for administration to patients for diagnosis or treatment of diseases.
The independent claims collectively cover the chemical structure of Evans Blue derivative conjugates, their linkage to therapeutic compounds, and their pharmaceutical formulations, providing a platform for long-acting therapeutics through albumin binding.
Stated Advantages
The system allows many small molecules and biologics to be modified in one step with high yield and purity.
The strong binding of the Evans Blue moiety to albumin enables control over in vivo biodistribution by adjusting the number of Evans Blue moieties and linkers.
The relatively small size of the Evans Blue moiety reduces the likelihood of interference with the biological function of the therapeutic drug candidate.
The invention provides an efficient method for developing long-lasting and long-acting drugs with high efficacy.
Documented Applications
Treatment or diagnosis of diabetes in mammals, including humans and non-human animals.
Treatment or diagnosis of cancer using albumin-based drug delivery systems.
Use in diagnostic imaging such as blood volume measurement and assessing permeability of biological barriers like the blood-brain barrier.
Interested in licensing this patent?