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-12233051-B2
Publication Date
2025-02-25
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 amount 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 is directed to methods of treating a patient having primary hyperoxaluria or idiopathic hyperoxaluria by administering a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salts, solvates, and hydrates thereof. These compounds act as lactate dehydrogenase (LDH) inhibitors and are useful in inhibiting the conversion of glyoxylate to oxalate. Treatment with these compounds prevents or substantially reduces the accumulation of oxalate in the patient's kidneys, bladder, urinary tract, and other organs.
Primary hyperoxalurias (PHs) are rare autosomal recessive disorders caused by overproduction of oxalate leading to recurrent calcium oxalate kidney stone disease and potentially fatal end-stage renal disease. PH type 1, type 2, and type 3 result from mutations in genes encoding enzymes involved in glyoxylate metabolism. Current treatments include liver-kidney or kidney transplantation. LDH is a key enzyme responsible for converting glyoxylate to oxalate. The problem being solved is the need for orally available, potent, selective LDH inhibitors with adequate bioavailability for treating PH, as previous LDH inhibitors have had modest inhibition, poor cellular penetration, poor pharmacokinetics, and unsuitable tissue distribution profiles for hyperoxaluria treatment.
Claims Coverage
The patent includes multiple independent claims directed to methods of treating diseases associated with elevated oxalate levels using compounds of Formula I and related pharmaceutical compositions. The coverage presents the inventive features of these methods.
Use of specific compounds of Formula I to treat diseases with elevated oxalate levels
Methods involve administering therapeutically effective amounts of specific compounds of Formula I or pharmaceutically acceptable salts thereof to patients with diseases or disorders associated with elevated oxalate levels, including primary hyperoxaluria types 1, 2, and 3, idiopathic hyperoxaluria, kidney stone disease, chronic kidney disease (CKD), and end stage renal disease (ESRD). The compounds inhibit lactate dehydrogenase (LDH) activity to reduce oxalate levels.
Reduction of oxalate concentration and LDH activity in patients
The methods specify administration of amounts sufficient to reduce the concentration of oxalate in the patient’s urine or blood compared to pre-administration levels and/or reduce LDH activity in the patient's liver compared to pre-administration levels.
Decreasing kidney stone size and number
The methods include administering compounds in amounts sufficient to decrease the mean size of kidney stones or the total number of kidney stones in the patient's kidneys compared to pre-treatment measurements.
Treatment of genetically defined hyperoxaluria
The methods apply to patients having mutations in AGXT, GPHPR, HOGA1, or combinations thereof, addressing specific genetic causes of primary hyperoxaluria using the compounds of Formula I.
Administration as monotherapy or combination therapy
The compounds of Formula I can be administered alone as monotherapy or in combination with additional active agents, such as Vitamin B-6, phosphate, citrate, stiripentol (DIACOMIT), freeze-dried live Oxalobacter formigenes (OXABACT), reloxaliase (ALLN-177), and RNA interference agents (RNAi).
The claims provide coverage for novel pharmaceutical methods using specific Formula I compounds and their salts to treat conditions associated with elevated oxalate levels by inhibiting LDH, reducing oxalate levels, decreasing kidney stone burden, targeting genetic forms of hyperoxaluria, and optionally using combination therapies to enhance treatment efficacy.
Stated Advantages
The compounds can potentially eliminate the need for liver and kidney transplants in PH patients by reducing oxalate production.
They prevent calcium oxalate deposits, thereby preventing kidney and liver damage.
The inhibitors improve quality of life and length of life for patients suffering from primary hyperoxaluria.
The agents have liver-targeted tissue distribution with improved hepatocyte activity and minimal cytotoxicity, suitable for hyperoxaluria treatment compared to previous oncology-focused LDH inhibitors.
Documented Applications
Treating primary hyperoxaluria types 1, 2, and 3.
Treating idiopathic hyperoxaluria.
Treating diseases or disorders associated with elevated oxalate levels including hyperoxaluria, chronic kidney disease (CKD), end stage renal disease (ESRD), and kidney stone disease.
Preventing and reducing kidney stone formation and treating kidney disease in patients with idiopathic calcium oxalate kidney stone disease or undefined primary hyperoxaluria.
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