Compositions and methods of modulating short-chain dehydrogenase activity
Inventors
Markowitz, Sanford • Ready, Joseph • Gwaltney, II, Stephen L. • Antczak, Monika
Assignees
Case Western Reserve University • University of Texas System • Rodeo Therapeutics Inc
Publication Number
US-12336982-B2
Publication Date
2025-06-24
Expiration Date
2039-11-21
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Abstract
Compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and/or prostaglandin levels include 15-PGDH inhibitors described herein.
Core Innovation
The invention relates to compounds and methods for modulating short-chain dehydrogenase (SCD) activity, specifically 15-hydroxy-prostaglandin dehydrogenase (15-PGDH), in order to modulate tissue prostaglandin levels and to treat diseases, disorders, or conditions where modulation of 15-PGDH activity and/or prostaglandin levels is desirable. The core compounds are 15-PGDH inhibitors having specific chemical structures defined by various formulae (IA, I, II, III, IV, V, VI, VII, VIII) with detailed variations in substituent groups, and may include their pharmaceutically acceptable salts, tautomers, or solvates.
The background identifies the problem that SCDs, including 15-PGDH, are involved in the synthesis and degradation of fatty acids, steroids, and prostaglandins, implicating them in disorders like lipid storage disease, myopathy, SCD deficiency, genetic disorders, and diseases such as ulcerative colitis and gastrointestinal ulcers. 15-PGDH serves as a key enzyme for inactivating active prostaglandins; thus, modulating its activity could provide therapeutic benefits such as tissue regeneration, wound healing, and treatment of inflammatory and fibrotic diseases.
The invention addresses these problems by providing inhibitors that can be administered topically, orally, intravenously, or via other routes, to increase prostaglandin levels in tissues or blood, thereby promoting desired biological processes such as tissue repair, hair growth, bone formation, mitigation of tissue graft rejection, and treating diseases where prostaglandin modulation is beneficial. The invention further describes pharmaceutical and cosmetic compositions containing these inhibitors for a wide range of therapeutic and cosmetic applications.
Claims Coverage
The patent contains several independent claims, focusing on chemical compounds, pharmaceutical compositions, and treatment methods relating to the modulation of 15-PGDH activity.
15-PGDH inhibitor compounds of Formula (IA)
A compound of Formula (IA) or its pharmaceutically acceptable salt, tautomer, or solvate, wherein the substituents R1, R2, R6, R7, R3, R4, R5, R8, R9, R10, X, m, n, and t are defined with a range of structural and functional chemical groups. The claim encompasses these compounds with detailed options for each substituent group, covering a broad structural class of 15-PGDH inhibitors.
Pharmaceutical composition containing a 15-PGDH inhibitor
A pharmaceutical composition comprising a compound, salt, or solvate as defined in the chemical claims (e.g., of Formula (IA)), together with a pharmaceutically acceptable excipient or carrier. This includes compositions intended for use as drugs based on the described 15-PGDH inhibitors.
Method of treating inflammatory bowel disease using a 15-PGDH inhibitor
A method of treating inflammatory bowel disease (IBD) in a human subject by administering a therapeutic amount of a compound of Formula (IA), including defined embodiments for treating specific IBD types such as Crohn's Disease using selected compounds.
Method of cell therapy using 15-PGDH inhibitor
A method of treating a human subject in need of cell therapy by administering a therapeutically effective amount of a preparation comprising human hematopoietic stem cells combined with a defined 15-PGDH inhibitor compound, salt, or solvate.
Method of treating ischemic tissue or tissue damaged by ischemia using 15-PGDH inhibitors
A method of treating a human subject having at least one symptom associated with an ischemic tissue or tissue damaged by ischemia, comprising administering a therapeutically effective amount of a 15-PGDH inhibitor compound, salt, or solvate.
Method of increasing or mobilizing hematopoietic stem cells and neutrophils using a 15-PGDH inhibitor
Methods for increasing neutrophil counts, increasing or mobilizing peripheral blood hematopoietic stem cells, or increasing the numbers of hematopoietic stem cells in blood or bone marrow of a human subject by administration of a therapeutically effective amount of a 15-PGDH inhibitor compound, salt, or solvate.
Method for treating or preventing fibrotic disease using a 15-PGDH inhibitor
A method of treating or preventing a fibrotic disease, disorder, or condition in a human subject by administering a therapeutically effective amount of a 15-PGDH inhibitor compound, salt, or solvate.
Method for treating inflammation or reducing immune activity with a 15-PGDH inhibitor and corticosteroid
A method of treating inflammation or reducing the activity of the immune system in a human subject by administering a therapeutically effective amount of a 15-PGDH inhibitor compound, salt, or solvate in combination with a corticosteroid.
Method of treating glucocorticoid insensitivity with 15-PGDH inhibitor and corticosteroid
A method for the treatment of glucocorticoid insensitivity, restoring corticosteroid sensitivity, enhancing glucocorticoid sensitivity, or reversing the glucocorticoid insensitivity in a human subject experiencing corticosteroid dependence, corticoid resistance, or intolerance, by administering a pharmaceutical composition comprising a 15-PGDH inhibitor and a corticosteroid.
The independent claims broadly cover specific 15-PGDH inhibitor compounds, their pharmaceutical compositions, and therapeutic methods for treating a variety of conditions—especially diseases involving prostaglandin regulation, inflammatory, fibrotic, and immune-related disorders.
Stated Advantages
The 15-PGDH inhibitors described provide a pharmacologic method for elevating prostaglandin levels in tissue, leading to benefits in promoting hair growth, skin pigmentation, and wound healing.
The compounds can be used to increase tissue stem cell numbers, improving resistance to tissue damage by radiation and the fitness of bone marrow or other transplantation tissues.
The inhibitors may promote liver regeneration after surgery or toxic insults such as acetaminophen overdose.
They can protect from intestinal injury, such as chemotherapy-induced mucositis and radiation toxicity.
Compounds exhibit improved human and mouse microsome stability compared to previously disclosed 15-PGDH inhibitors, resulting in longer duration of therapeutic effect.
Certain structural modifications can improve hERG inhibition profile, solubility, and pharmacokinetic properties.
The invention offers methods for improving stem cell mobilization and engraftment, reducing graft rejection, and enhancing recovery of blood cell lineages after transplantation or cytotoxic therapies.
The inhibitors can be administered in combination with corticosteroids or TNF inhibitors to enhance anti-inflammatory and immunosuppressive effects while reducing adverse or cytotoxic effects.
Administration can allow corticosteroids to be used at lower dosages for similar effects, or at higher dosages with reduced side effects.
The compounds have lower EC50 values for induction of PGE2, allowing for higher potency and efficacy in elevating prostaglandin levels.
Documented Applications
Promotion of hair growth and prevention of alopecia by inhibiting 15-PGDH in scalp tissue.
Stimulation of skin pigmentation and prevention or limitation of skin depigmentation—including prevention of canities.
Wound healing and treatment of skin damage or inflammation, including healing of dermal wounds, ulcers, and burns.
Treatment and prevention of cardiovascular diseases and vascular insufficiency, such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary artery hypertension.
Promotion of tissue repair, regeneration, and stem cell mobilization for hematopoietic or other tissue stem cell transplantation.
Treatment of oral ulcers, gum disease, colitis, ulcerative colitis, gastrointestinal ulcers, and inflammatory bowel disease.
Enhancement of tissue and bone marrow graft engraftment, and mitigation of rejection following transplantation.
Increasing counts of neutrophils, platelets, and red blood cells in subjects with cytopenias due to chemotherapy, radiation, bone marrow disorders, or viral infection.
Treatment of bone-associated conditions including increasing bone density, treating osteoporosis, and promoting healing of fractures or healing after bone/bone or bone/implant surgery.
Increasing liver regeneration after surgery, transplantation, toxin exposure, or live liver donation.
Treatment of erectile dysfunction.
Inhibition of growth, proliferation, or metastasis of 15-PGDH-expressing cancers.
Treatment or prevention of a broad range of ischemic conditions and tissue types, including heart, limb, brain, kidney, lung, and gastrointestinal tract.
Combination therapy with G-CSF, hemopoietic cytokines, and/or Plerixafor to increase neutrophil counts or mobilize hematopoietic stem cells for transplantation.
Treatment or prevention of fibrosis and various fibrotic diseases or conditions—including pulmonary fibrosis, kidney fibrosis, liver fibrosis, heart fibrosis, scleroderma, and systemic sclerosis.
Reduction and prevention of scar formation on skin, reduction of hypertrophic scars, keloids, and atrophic scars.
Combination therapy with corticosteroids or TNF inhibitors for enhanced anti-inflammatory, immunosuppressive, or tissue repair effects including treatment of glucocorticoid insensitivity.
Use in cosmetic compositions for topical application to skin or hair, including hair creams, lotions, shampoos, and mascaras for hair or eyelashes.
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