Selective proton coupled folate transporter and folate receptor, and GARFTase inhibitor compounds and methods of using the same
Inventors
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Assignees
Wayne State University • Duquesne University of the Holy Spirit
Member
Nanomedicine Manufacturing Lab, Duquesne UniversityNANOMEDICINE MANUFACTURING LABORATORY
Nanomedicine Manufacturing Laboratory (NML) is a research and development laboratory specializing in nanomaterials and biomaterials for imaging, oxygen delivery, and drug delivery, with a core emphasis on scalable manufacturing and Quality-by-Design (QbD).
More informaiton about NML: https://www.duq.edu/research/faculty-research/nanomedicine-lab/nanomed-lab-research.php
Led by Dr. Jelena M. Janjic, the Nanomedicine Manufacturing Laboratory develops colloidal nanosystems and implantable biomaterials that support molecular imaging modalities, including magnetic resonance imaging (MRI) and near-infrared fluorescence; biosensing, drug delivery; oxygen delivery; and theranostic nanomaterials, used for local and parenteral administration or as implantable biomaterials.
A major barrier to the advancement of nanotechnology-based therapeutics is not conceptual innovation but manufacturability, cost, and quality control. The Nanomedicine Manufacturing Laboratory addresses these challenges by incorporating manufacturing process design, scalability, and quality control at the earliest stages of material design. Over the past decade, the laboratory has established robust, reproducible, and cost-effective nanomedicine manufacturing methods by applying QbD frameworks, enabling reliable scale-up and controlled performance.
The laboratory’s work is supported by the U.S. Air Force, the Congressionally Directed Medical Research Programs (CDMRP), and ARPA-H through collaborative programs spanning academia, industry, and government. The Nanomedicine Manufacturing Laboratory operates at the intersection of materials science, manufacturing, and translational medicine, with a focus on developing innovative nanomedicines and biomaterials that translate into accessible, cost-effective future treatments for civilian and military medical needs.
NANOMEDICINE MANUFACTURING LABORATORY Nanomedicine Manufacturing Laboratory (NML) is a research and development laboratory specializing in nanomaterials and biomaterials for imaging, oxygen delivery, and drug delivery, with a core emphasis on scalable manufacturing and Quality-by-Design (QbD). More informaiton about NML: https://www.duq.edu/research/faculty-research/nanomedicine-lab/nanomed-lab-research.php Led by Dr. Jelena M. Janjic, the Nanomedicine Manufacturing Laboratory develops colloidal nanosystems and implantable biomaterials that support molecular imaging modalities, including magnetic resonance imaging (MRI) and near-infrared fluorescence; biosensing, drug delivery; oxygen delivery; and theranostic nanomaterials, used for local and parenteral administration or as implantable biomaterials. A major barrier to the advancement of nanotechnology-based therapeutics is not conceptual innovation but manufacturability, cost, and quality control. The Nanomedicine Manufacturing Laboratory addresses these challenges by incorporating manufacturing process design, scalability, and quality control at the earliest stages of material design. Over the past decade, the laboratory has established robust, reproducible, and cost-effective nanomedicine manufacturing methods by applying QbD frameworks, enabling reliable scale-up and controlled performance. The laboratory’s work is supported by the U.S. Air Force, the Congressionally Directed Medical Research Programs (CDMRP), and ARPA-H through collaborative programs spanning academia, industry, and government. The Nanomedicine Manufacturing Laboratory operates at the intersection of materials science, manufacturing, and translational medicine, with a focus on developing innovative nanomedicines and biomaterials that translate into accessible, cost-effective future treatments for civilian and military medical needs.
Publication Number
US-10000498-B2
Publication Date
2018-06-19
Expiration Date
2028-10-01
Abstract
Fused cyclic pyrimidine compounds, including tautomers thereof, and pharmaceutically acceptable salts, prodrugs, solvates and hydrates thereof, are disclosed having the general Formula I: These compounds are useful in methods for treating cancer, selectively targeting cancerous cells via the proton coupled folate transporter, folate receptor alpha, and/or folate receptor beta pathways, inhibiting GARFTase in cancerous cells, and selectively targeting activated macrophages in a patient having an autoimmune disease, such as rheumatoid arthritis.
Core Innovation
The invention provides fused cyclic pyrimidine compounds, particularly those described by Formula I and its pharmaceutically acceptable salts, prodrugs, solvates, and hydrates. These compounds are characterized by specific substituents, including heterocycloalkyl-carbonyl-L-glutamate or heterocycloaryl-carbonyl-L-glutamate side chains. The compounds demonstrate selective activity through the proton-coupled folate transporter (PCFT), folate receptor alpha (FRα), or folate receptor beta (FRβ) pathways, and function as inhibitors of glycinamide ribonucleotide formyltransferase (GARFTase) in cancerous cells.
A significant limitation of current antifolate chemotherapeutics is their lack of selectivity, which results in toxicity to normal cells due to uptake via the ubiquitous reduced folate carrier (RFC) system. Prior folic acid-based therapeutics either require chemical cleavage to activate a cytotoxic agent or suffer from premature release, leading to off-target toxicity or diminished anti-tumor effectiveness. The present invention addresses these issues by designing compounds that are preferentially transported into tumor cells via PCFT and FRs, but not via RFC, thus minimizing toxicity to normal tissues.
The invention also extends to methods for using the disclosed compounds for treating cancer, targeting cancerous cells expressing PCFT and FRs, inhibiting GARFTase within such cells, and selectively targeting activated macrophages in autoimmune diseases, such as rheumatoid arthritis. Pharmaceutical compositions and methods for administration, including various routes and forms, are also disclosed as integral parts of the invention.
Claims Coverage
The patent contains multiple independent claims directed to novel chemical compounds, pharmaceutical compositions, and methods of use based on two core chemical formulas.
Fused cyclic pyrimidine compounds of Formula I
The invention claims compounds of Formula I, defined by specific structural features including: - Substituents at positions R1, R2, R3, R4, and R5 (with specified possible chemical groups for each). - A core structure where A can be CR'R'', NR', S, or O. - The five-membered ring possesses a side chain attached at positions 5, 6, or 7. - X is a heterocycloalkyl-carbonyl-L-glutamate group, heterocycloaryl-carbonyl-L-glutamate group, or hydrogen, with further definition for R4 depending on X. - The sum of y and z (side chain carbon atoms) is less than or equal to seven. - Claim covers tautomers and all pharmaceutical salts, prodrugs, solvates, and hydrates thereof.
Pharmaceutically acceptable salts of Formula I compounds
The scope includes pharmaceutically acceptable salts of the Formula I compounds, providing the same structural specificity as the parent compounds.
Pharmaceutical compositions containing Formula I compounds
The claims cover pharmaceutical compositions comprising a therapeutically effective amount of a Formula I compound or its pharmaceutically acceptable salt.
Fused cyclic pyrimidine compounds of Formula II
The invention claims compounds of Formula II, defined similarly to Formula I but with variations including: - R1 is hydrogen or C1–C6 alkyl. - R2, R3, and A have specified groups, with B as S, O, or N. - The five-membered ring has a side chain at position 6, and the bond at position 5-6 is double. - y is an integer from zero to seven, with scope encompassing tautomers, salts, prodrugs, solvates, and hydrates.
Pharmaceutical compositions containing Formula II compounds
The claims include pharmaceutical compositions with a therapeutically effective amount of a Formula II compound or its pharmaceutically acceptable salt.
The inventive features focus on the design and use of highly selective fused cyclic pyrimidine compounds, pharmaceutical compositions thereof, and specific substitutions and side chain characteristics as defined by Formula I and II, along with their pharmaceutically acceptable derivatives.
Stated Advantages
The compounds selectively target cancerous cells via proton coupled folate transporter and folate receptor pathways, minimizing toxicity to normal tissues.
The compounds effectively inhibit GARFTase in cancerous cells, leading to growth inhibition and lysis of target cancer cells.
The invention provides a means to selectively target activated macrophages in autoimmune diseases, such as rheumatoid arthritis, with minimal effects on normal cells.
The compounds exhibit negligible substrate activity for the ubiquitous reduced folate carrier, thereby reducing off-target effects and enhancing tumor selectivity.
Pharmaceutical compositions can be formulated in a wide variety of routes and forms for improved administration and dosing flexibility.
Documented Applications
Treatment of cancer, including targeting cancer cells that express proton coupled folate transporter and/or folate receptor alpha or beta.
Inhibition of glycinamide ribonucleotide formyltransferase (GARFTase) activity in cancerous cells.
Selective targeting of activated macrophages in a patient having an autoimmune disease, specifically rheumatoid arthritis.
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