Substituted pyrazolo[4,3-D]pyrimidines as gut-targeted phosphodiesterase inhibitors
Inventors
BROWNING, Darren • Lebedyeva, Iryna
Assignees
Augusta University • Augusta University Research Institute Inc
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Publication Number
US-12662485-B2
Publication Date
2026-06-23
Expiration Date
Abstract
Provided herein are compounds that inhibit phosphodiesterase 5 (PDE5) and methods of use thereof. In some forms, the compounds can have a structure according to Formula I: Also provided are pharmaceutical compositions and medicaments that include the compounds described herein as well as methods of treating gastrointestinal diseases and disorders such as intestinal cancers, chronic constipation, and inflammatory bowel disease.
Core Innovation
The invention relates to gut-localized phosphodiesterase 5 (PDE5) inhibitor small molecules and gut-targeted PDE5 inhibitor concepts using compounds of Formula I, including pharmaceutically acceptable salts, solvates, stereoisomers, and tautomers. The compounds are intended to remain in the gastrointestinal tract, be retained in intestinal epithelial cells, and increase intestinal epithelial cGMP to activate downstream PKG signaling.
The disclosed approach uses structural constraints and non-RO5 design principles, including polar or charged substituents, to reduce LogD leakage and improve gut interaction. The invention recites chemical scaffold embodiments for Formula I, Formula II, and Formula III, including desmethyl sildenafil analogs, related polar analog concepts, carboxylic-acid-bearing malonyl-sildenafil concepts, boronyl/triazole-COOH concepts, and prodrug concepts intended for activation in the intestinal environment.
The document also describes pharmaceutical compositions and formulations for these compounds, including immediate, extended, delayed release, and enteric-release dosage forms, as well as enteral, rectal, and transdermal routes. Controlled-release systems using carriers and polymeric or nanoparticle/microparticle systems are described in connection with gut-localized activity, and the nonclinical assessment components include a sildenafil analog permeability rationale, a reporter cell assay concept, and in vivo mouse measurements.
Claims Coverage
The independent claims are directed to Formula I compounds or their pharmaceutically acceptable derivative forms. The main inventive features are structural constraints on the variable substituents, including fixed X = —O— and enumerated C(O)-containing R4 options, with additional narrowing in some claims by specific selections for R1, R2, R3, R6, R7, R8, R9, R10, and n.
Formula I compound framework with constrained variable groups
A compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, with R1, R2, and R3 selected from specified C1-10 alkyl, OC1-10 alkyl, C3-10 cycloalkyl, aryl, or heteroaryl options with optional substituents; X is —O—; and R4 and associated R6-R10/n are defined by listed C(O)-containing options and related constraints.
Formula I with restricted R1, R2, R3 as C1-10 alkyl and X = —O—
A compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R1, R2, and R3 are C1-10 alkyl; X is —O—; R4 is selected from enumerated C(O)-containing substituent structures; R6 and R7 are H or C1-10 alkyl; R8, R9, and R10 are C1-10 alkyl; and n is 1, 2, 3, 4, 5, or 6.
The independent claims define Formula I gut-localized PDE5 inhibitor compounds in pharmaceutically acceptable derivative forms through explicit structural constraints, with X fixed as —O— and R4 limited to enumerated C(O)-containing options. Dependent claims further narrow coverage by selecting specific R4 substituent structures, including C(O)CH2C(O)OH, and by specifying a particular chemical structure set referenced by the provided identifiers.
Stated Advantages
Retains PDE5 inhibitor compounds in the gut by reducing LogD leakage and improving gut interaction.
Enables elevated cGMP and PKG activity in intestinal mucosa to normalize motility.
Repairs intestinal epithelial barrier function.
Reduces intestinal neoplasia, including chronic constipation and colorectal cancer.
Reduced plasma entry.
Preserved PDE5 inhibitory activity in a PKG2/PDE5 reporter system.
Reduced colon epithelial proliferation (Ki67).
Improved constipation transit.
Enhanced barrier function (FITC-dextran reduction).
Documented Applications
Treating and/or preventing GI disorders, including chronic constipation and colorectal cancer, using gut-localized PDE5 inhibitor small molecules as substitutes for systemic PDE5 inhibitors.
Prevention or slowing of colorectal/intestinal cancer and intestinal neoplasia, based on the described effects of gut-targeted PDE5 inhibition and downstream PKG signaling.
Improving intestinal barrier function (luminal integrity) in disorders including IBS and inflammatory bowel disease.
Use in disorders associated with constipation, including opioid-induced constipation.
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