Treating primary or idiopathic hyperoxaluria with small molecule inhibitors of lactate dehydrogenase
Inventors
Hall, Matthew • Urban, Daniel J. • Knight, John • Holmes, Ross • Wood, Kyle David • Waterson, Alex • DARLEY-USMAR, Victor M. • Neckers, Leonard M.
Assignees
UAB Research Foundation • Vanderbilt University • US Department of Health and Human Services
Publication Number
US-11752138-B2
Publication Date
2023-09-12
Expiration Date
2041-05-17
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Abstract
The disclosure provides methods of treating a patient having primary hyperoxaluria or idiopathic hyperoxaluria comprising administering a therapeutically effective amound of compound of the formula and pharmaceutically acceptable salts, solvates, and hydrates thereof to the patient. The variables, e.g. ring A, n, R, R3, R10, X, Y, and Z are defined herein. These compounds act as lactate dehydrogenase inhibitors and are useful inhibiting the conversion of glyoxylate to oxalate. When administered to a patient having a disease or disorder associated with elevated oxalate levels, such as PH type 1, type 2, or type 3 or idiopathic hyperoxaluria the compounds prevent or substantially reduce the amount and buildup of oxalate the patient's kidneys, bladder, urinary tract and other parts of the patient's body.
Core Innovation
The invention provides methods of treating patients having primary hyperoxaluria or idiopathic hyperoxaluria by administering a therapeutically effective amount of compounds of the formula provided (Formula I), including pharmaceutically acceptable salts, solvates, and hydrates thereof. These compounds act as lactate dehydrogenase inhibitors and are useful in inhibiting the conversion of glyoxylate to oxalate, which prevents or substantially reduces the amount and buildup of oxalate in the kidneys, bladder, urinary tract, and other parts of the patient's body.
Primary hyperoxalurias (PHs) are rare autosomal recessive disorders characterized by the overproduction of oxalate leading to recurrent calcium oxalate kidney stone disease and potentially end-stage renal disease. PH type 1, 2, and 3 each involve mutations in distinct enzymes responsible for glyoxylate metabolism. Excess glyoxylate is converted to oxalate, which accumulates and causes damage to kidneys, liver, and other organs. Current treatments include liver and kidney transplantation, but there is a need for therapeutics that can reduce oxalate production without transplantation.
The disclosed compounds, as potent and selective orally available lactate dehydrogenase (LDH) inhibitors, address shortcomings of prior LDH inhibitors which suffered from modest inhibition, poor cellular penetration, and poor pharmacokinetic properties. Unlike oncology applications requiring systemic distribution of LDH inhibitors, treating hyperoxaluria demands liver-targeted distribution with improved activity in hepatocytes and minimal cytotoxicity. This invention thus provides a need for orally available LDH inhibitors with sufficient selectivity, potency, and bioavailability for the treatment of primary and idiopathic hyperoxaluria.
Claims Coverage
The claims cover multiple inventive features related to methods of treating diseases associated with elevated oxalate levels by administering compounds of Formula I or Formula II, including their pharmaceutically acceptable salts, solvates, and hydrates.
Method of treating diseases associated with elevated oxalate levels using compounds of Formula I
Administering a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt, solvate, or hydrate thereof to a patient to treat diseases or disorders associated with elevated oxalate levels such as primary hyperoxaluria or idiopathic hyperoxaluria.
Specific structural features of compounds of Formula I for treatment
Using compounds where X is hydrogen or fluoro, Y is hydrogen, Z is —CO2H, and R10 is (cyclopropyl)C0-C2alkyl, with additional features involving the A ring as phenyl, halogen substituents, and R3 groups defined as phenyl or -L-Q with specific heterocyclic substituents.
Method of preventing or reducing symptoms of primary hyperoxaluria based on gene mutation detection
Determining a patient has a mutation causing loss or reduction of enzyme function in alanine-glycolate aminotransferase (AGXT), glyoxylate reductase/hydroxypyruvate reductase (GPHPR), or 4-hydroxy-2-oxoglutarate aldolase 1 (HOGA1), then administering a therapeutically effective amount of a compound of Formula I or its salts, solvates, or hydrates.
Method of treating disease with compounds of Formula II and Formula II-A
Administering therapeutically effective amounts of compounds of Formula II or Formula II-A and their pharmaceutically acceptable salts, solvates, or hydrates to treat diseases or disorders associated with elevated oxalate levels, with further structural and substitutional specifications including R10 as (cyclopropyl)C0-C2alkyl.
Therapeutically effective amount sufficient to reduce oxalate and LDH activity, and decrease kidney stone size or number
Administering a therapeutically effective amount of compounds to significantly reduce oxalate concentration in urine or blood, reduce LDH activity in the liver, and decrease the mean size or total number of kidney stones in the kidneys.
Treatment of specific diseases and gene mutation carriers
Treating primary hyperoxaluria types 1, 2, and 3, idiopathic hyperoxaluria, kidney stone disease, chronic kidney disease, and end-stage renal disease, especially in patients carrying AGXT, GPHPR, or HOGA1 mutations or combinations thereof.
Administration as monotherapy or combination therapy
Administering compounds of Formula I or salts, solvates, or hydrates thereof as monotherapy or in combination with additional active agents such as Vitamin B-6, phosphate, citrate, stiripentol, freeze-dried live Oxalobacter formigenes, reloxaliase, or RNAi therapies.
Varied administration routes and specific compounds
Administering compounds orally, sublingually, by injection, or inhalation, including specific exemplified compounds of Formula I detailed in the patent.
The claims comprehensively cover methods of treating and preventing diseases associated with elevated oxalate levels using specified compounds of Formula I and II, including their structural variants, effective dosing regimens, and modes of administration, with options for monotherapy or combination therapy targeting primary and idiopathic hyperoxaluria and related kidney diseases.
Stated Advantages
Oral administration of LDH small molecule inhibitors can remove the need for liver and kidney transplants in primary hyperoxaluria patients.
The compounds prevent calcium oxalate deposits and subsequent kidney and liver damage by inhibiting oxalate overproduction.
The disclosed LDH inhibitors show improved potency, selectivity, cellular penetration, and pharmacokinetic properties over prior art compounds.
Agents are liver-targeted with enhanced hepatocyte activity and minimal cytotoxicity, meeting the specific distribution requirement for treating hyperoxaluria.
Use of these compounds can improve length and quality of life for hyperoxaluria patients by reducing oxalate levels and kidney stone formation.
Documented Applications
Treatment of primary hyperoxaluria types 1, 2, and 3.
Treatment of idiopathic hyperoxaluria and idiopathic calcium oxalate kidney stone disease.
Treatment and prevention of kidney disease and kidney stone formation associated with elevated oxalate levels.
Treatment of chronic kidney disease (CKD), end-stage renal disease (ESRD), and kidney stone disease associated with elevated oxalate.
Prevention or reduction of symptoms in patients with mutations in genes encoding the enzymes AGXT, GPHPR, or HOGA1 associated with hyperoxaluria.
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