Selective proton coupled folate transporter and folate receptor, and garftase inhibitor compounds and methods of using the same
Inventors
Gangjee, Aleem • Matherly, Larry H.
Assignees
Wayne State University • Duquesne University of the Holy Spirit
Publication Number
US-11053252-B2
Publication Date
2021-07-06
Expiration Date
2028-10-01
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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 present invention relates to selective proton coupled folate transporter (PCFT) and alpha and beta folate receptor (FR) and glycinamide ribonucleotide formyltransferase (GARFTase) enzyme inhibitor compounds of the fused cyclic pyrimidine class, exemplified by those with specific heterocycloalkyl-carbonyl-L-glutamate or heterocycloaryl-carbonyl-L-glutamate substituents. These compounds are described by Formula I and include tautomers, pharmaceutically acceptable salts, prodrugs, solvates, and hydrates. The invention provides pharmaceutical compositions with these compounds for treating cancer by targeting select molecular pathways.
A significant problem in cancer chemotherapy is the lack of selectivity of known agents, which target both normal and cancerous cells, leading to cytotoxicity in healthy tissues and limited effectiveness against advanced or drug-resistant tumors. Existing folate-based therapeutics often fail to selectively target tumor cells because they are taken up by both the ubiquitous reduced folate carrier (RFC) system and folate receptors, resulting in undesirable toxicity. Additionally, the delivery of cytotoxic agents using folate conjugates faces challenges related to the release mechanism, compromising anti-tumor activity or causing premature toxicity.
The invention addresses this need by providing single compounds that exhibit potent anti-tumor activity through selective targeting of FR alpha and FR beta on cancer cells, inhibiting GARFTase, and having negligible activity as substrates for RFC. These compounds also enable selective targeting of cancerous cells via the PCFT pathway and activated macrophages in autoimmune diseases such as rheumatoid arthritis. Experimental results illustrate that the compounds of Formula I exhibit strong selectivity and cytotoxicity for FR-expressing tumor cells, minimal activity in RFC-expressing cells, and effective GARFTase inhibition, thus providing more targeted therapeutic options.
Claims Coverage
There are four independent claims, each defining a core inventive feature related to the compound of Formula I or its pharmaceutical compositions.
Compound of Formula I
A compound having Formula I, wherein: - R1, R2, R3, R4, and R5 are defined and selected from specific groups including hydrogen, alkyl, hydroxyl, and various substituted and unsubstituted groups as explicitly stated. - A represents CR′R″, NR′, sulfur, or oxygen, with R′ and R″ as hydrogen or alkyl (1 to 6 carbons). - The five-membered ring in the compound may have a side chain attached at positions 5, 6, or 7 with detailed attachment options based on the position and identity of A. - X is a heterocycloalkyl-carbonyl-L-glutamate group, heterocycloaryl-carbonyl-L-glutamate group, or hydrogen, with R4 complementing X as described in detail. - The compound allows for multiple configurations of side chains, including variations in single/double bonds, alkyl substitutions, and integer ranges for y and z.
Preferred side chain attachment in compound of Formula I
A compound of Formula I as specified above, wherein: - The side chain attachment is at carbon atom position 6. - A is CR′R″. - The carbon atom at position 5 independently has either two hydrogen atoms (if the 5-6 bond is a single bond), one hydrogen atom (if the 5-6 bond is double), or an alkyl group (one to six carbons) with a hydrogen atom (single bond between 5 and 6) or just an alkyl group (double bond).
Pharmaceutical composition containing compound of Formula I
A pharmaceutical composition comprising: - A therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt of Formula I as fully specified. - Optionally includes the compounds with side chain attachments at defined positions and using the defined substituents and structural requirements.
Pharmaceutical composition with specified side chain position
A pharmaceutical composition comprising: - A therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt of Formula I, where: - The side chain is attached at carbon atom position 6. - A is CR′R″. - The carbon atom at position 5 independently has attached two hydrogen atoms or an alkyl group as determined by the bond order (single or double) between carbons 5 and 6, with all substituent options for side chains as defined in the claim.
The independent claims collectively cover the novel compounds of Formula I with specific substitutions and structural features, along with pharmaceutical compositions containing these compounds and configurations prioritizing side chain attachments and detailed substituents for therapeutic applications.
Stated Advantages
The compounds selectively target cancer cells by binding to FR alpha, FR beta, and/or PCFT and not being significantly taken up by the reduced folate carrier (RFC), resulting in greater tumor selectivity.
The compounds serve as potent inhibitors of GARFTase in cancerous cells, disrupting purine biosynthesis and effectively inhibiting tumor cell growth.
The invention enables selective targeting of activated macrophages in autoimmune disease, such as rheumatoid arthritis, reducing inflammation and tissue damage.
The compounds minimize toxicity to normal tissues compared to conventional antifolates, due to selective uptake by tumor-associated folate receptors and PCFT.
The invention addresses the challenge of premature or difficult release of cytotoxic agents from folate conjugates by providing compounds whose activity does not require cleavage from a carrier.
Documented Applications
Treating cancer by selectively targeting cancerous cells via the proton coupled folate transporter, folate receptor alpha, and/or folate receptor beta pathways.
Inhibiting glycinamide ribonucleotide formyltransferase (GARFTase) in cancerous cells to achieve cytotoxic effects in tumors.
Selective targeting of activated macrophages in patients with autoimmune diseases, such as rheumatoid arthritis.
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