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
Nanomedicines produced at NML include colloidal nanosystems for molecular imaging (magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging), targeted and local drug delivery, and imaging-supported drug delivery and theranostic nanomedicines and biomaterials. These products can be delivered locally, parenterally, or implanted into body cavities or wounds. Nanotechnology-based therapeutics are typically presented with high costs and challenging quality control, representing critical barriers to future clinical translation. In contrast, the offeror NML efforts over the past decade produced cost-effective, robust, and scalable manufacturing methods for nanomedicines with a high level of quality control by utilizing Quality-by-Design (QbD) approaches. Specifically, the application of QbD to nanomedicine manufacturing and quality control led to several firsts: 1) the first imaging-supported pain nanomedicine for trauma and surgical pain; 2) the first oxygen carrier with embedded imaging agents for real-time in line tracking during organ/limb preservation; 3) the first successful longitudinal immunomonitoring in non-human primates and porcine models using clinical grade imagers; 4) demonstrated nerve injury recovery following trauma by local nanomedicine implantation in rodents. NML also designs and produces biocompatible and multi-drug delivery hydrogels and biomaterials for multitude of applications, from supporting neuroregeneration to local immunosuppression and wound healing. Furthermore, NML successfully scaled up their laboratory protocols to produce >2L of nanoparticles/batch and evaluate them in human limb trials for oxygen delivery. The work in these areas has been supported by USAF and CDMRP contracts, which are highly collaborative and involve partners across academia, industry and Government. NML is currently funded by CDMRP and ARPA H.
Founded in 1878, Duquesne University is consistently ranked among the nation's top Catholic universities for its award-winning faculty and horizon-expanding education. Research happens in all fields across the University, from the humanities and sciences to health-related fields and business. This research is supported by the federal and state governments, foundations, and corporate partners. Duquesne's Pittsburgh location connects researchers of all kinds to a knowledge economy powered by large tech, medical, energy, and industrial sectors.
NANOMEDICINE MANUFACTURING LABORATORY Nanomedicines produced at NML include colloidal nanosystems for molecular imaging (magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging), targeted and local drug delivery, and imaging-supported drug delivery and theranostic nanomedicines and biomaterials. These products can be delivered locally, parenterally, or implanted into body cavities or wounds. Nanotechnology-based therapeutics are typically presented with high costs and challenging quality control, representing critical barriers to future clinical translation. In contrast, the offeror NML efforts over the past decade produced cost-effective, robust, and scalable manufacturing methods for nanomedicines with a high level of quality control by utilizing Quality-by-Design (QbD) approaches. Specifically, the application of QbD to nanomedicine manufacturing and quality control led to several firsts: 1) the first imaging-supported pain nanomedicine for trauma and surgical pain; 2) the first oxygen carrier with embedded imaging agents for real-time in line tracking during organ/limb preservation; 3) the first successful longitudinal immunomonitoring in non-human primates and porcine models using clinical grade imagers; 4) demonstrated nerve injury recovery following trauma by local nanomedicine implantation in rodents. NML also designs and produces biocompatible and multi-drug delivery hydrogels and biomaterials for multitude of applications, from supporting neuroregeneration to local immunosuppression and wound healing. Furthermore, NML successfully scaled up their laboratory protocols to produce >2L of nanoparticles/batch and evaluate them in human limb trials for oxygen delivery. The work in these areas has been supported by USAF and CDMRP contracts, which are highly collaborative and involve partners across academia, industry and Government. NML is currently funded by CDMRP and ARPA H. Founded in 1878, Duquesne University is consistently ranked among the nation's top Catholic universities for its award-winning faculty and horizon-expanding education. Research happens in all fields across the University, from the humanities and sciences to health-related fields and business. This research is supported by the federal and state governments, foundations, and corporate partners. Duquesne's Pittsburgh location connects researchers of all kinds to a knowledge economy powered by large tech, medical, energy, and industrial sectors.
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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