Bile acid-GCPII inhibitor conjugates to treat inflammatory diseases, including inflammatory bowel disease (IBD)
Inventors
SLUSHER, BARBARA • Peters, Diane E. • RAIS, RANA • Majer, Pavel • Tenora, Lukas • SNAJDR, Ivan
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Assignees
Institute Of Organic Chemistry & Biochemistry Av Cr VVI • Institute of Organic Chemistry and Biochemistry of ASCR vvi
MemberJohns Hopkins UniversityJohns Hopkins UniversityFounded in 1876, Johns Hopkins University is recognized as the first research university in the United States. It advances interdisciplinary education, high-impact research, and global outreach, supporting knowledge translation, technological innovation, and community partnerships. The university fosters academic excellence, innovation incubation, outreach, and inclusion across multiple campuses in Baltimore, integrating into the city's social, economic, and cultural life.
Founded in 1876, Johns Hopkins University is recognized as the first research university in the United States. It advances interdisciplinary education, high-impact research, and global outreach, supporting knowledge translation, technological innovation, and community partnerships. The university fosters academic excellence, innovation incubation, outreach, and inclusion across multiple campuses in Baltimore, integrating into the city's social, economic, and cultural life.
Publication Number
US-12698306-B2
Publication Date
2026-08-04
Expiration Date
Abstract
GCPII inhibitors comprising 2-(phosphonomethyl) pentanedioic acid (2-PMPA) conjugated to a bile acid and their use for treating a disease or condition associated with elevated levels of GCPII, including inflammatory bowel disease.
Core Innovation
The invention is directed to bile-acid GCPII inhibitor conjugate compounds and to conversion products described in the specification as phosphonic-acid analogs. GCPII (FOLH1) is described as overexpressed in inflammatory bowel disease with elevated GCPII activity, and the document defines GCPII inhibition in the context of these conjugate compounds and their binding-site interactions.
The core concept is linking a bile acid to a 2-PMPA moiety to create compounds intended to inhibit GCPII activity. The disclosed embodiments include compounds of formula (I) and pharmaceutically acceptable salts, with variable substituents R1-R4, representative bile acids, stereochemical variants, and representative labeled compounds.
The document further describes pharmaceutical compositions comprising the conjugates of formula (I) and pharmaceutically acceptable excipients, with optional inclusion of one or more additional therapeutic agents. It also presents assay and IC50 determination concepts and functional and in vivo evidence using a DSS colitis model, including changes in disease activity index, colon length, colon histology/ulcerations, reduced GCPII enzymatic activity, and changes in myeloid inflammatory populations.
Claims Coverage
The claims cover a compound selected from a group of compounds of formula (I) and pharmaceutically acceptable salts thereof, with additional claim scope directed to treating inflammatory bowel disease associated with elevated GCPII activity. The inventive features also include inhibition of GCPII activity in a subject, selection of Crohn’s disease or ulcerative colitis, and pharmaceutical compositions containing the compound with excipients and optionally additional therapeutic agents.
Selected compound group and pharmaceutically acceptable salts
A compound selected from the group of compounds of formula (I) and pharmaceutically acceptable salts thereof.
Treating inflammatory bowel disease associated with elevated GCPII activity
A method for treating a disease or condition associated with elevated GCPII activity by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a subject in need of treatment thereof.
Crohn’s disease or ulcerative colitis targeting
The inflammatory bowel disease is selected from Crohn’s disease or ulcerative colitis.
Inhibiting GCPII activity in the subject
In the method, the elevated GCPII activity is inhibited by administering the compound to the subject.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprises at least one compound of claim 1 in admixture with a pharmaceutically acceptable excipient.
Pharmaceutical composition with additional therapeutic agents
The pharmaceutical composition further comprises one or more additional therapeutic agents.
Across the claims, the invention is centered on compounds selected from the group of claim 1 with pharmaceutically acceptable salts and their use to treat inflammatory bowel disease associated with elevated GCPII activity by inhibiting GCPII activity, with coverage for pharmaceutical compositions that include excipients and optionally one or more additional therapeutic agents.
Stated Advantages
Reduced IBD severity is linked to GCPII inhibition in disease conditions associated with elevated GCPII activity.
Treating inflammatory bowel disease associated with elevated GCPII activity.
Inhibits GCPII activity in the subject.
Includes pharmaceutical compositions with pharmaceutically acceptable excipients.
Allows inclusion of one or more additional therapeutic agents.
Documented Applications
Treating inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, associated with elevated GCPII activity by administering a therapeutically effective amount of a claimed GCPII inhibitor conjugate compound or a pharmaceutically acceptable salt thereof.
Use of pharmaceutical compositions comprising a claimed compound with a pharmaceutically acceptable excipient for treatment, including compositions further comprising one or more additional therapeutic agents.
Treatment methods for inflammatory bowel disease associated with elevated GCPII activity, including Crohn’s disease and ulcerative colitis.
Pharmaceutical compositions comprising at least one compound of the group with a pharmaceutically acceptable excipient, and optionally one or more additional therapeutic agents.
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