PHD inhibitor compounds, compositions, and use
Inventors
Fleming, Paul E. • Blaisdell, Thomas P. • Allu, Senkara Rao
Assignees
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Publication Number
US-12753161-B2
Publication Date
2026-10-06
Expiration Date
Abstract
The present invention provides, in part, novel small molecule inhibitors of PHD, having a structure according to Formula (A), and sub-formulas thereof: or a pharmaceutically acceptable salt thereof. The compounds provided herein can be useful for treatment of diseases including heart (e.g. ischemic heart disease, congestive heart failure, and valvular heart disease), lung (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver (e.g. acute liver failure and liver fibrosis and cirrhosis), and kidney (e.g. acute kidney injury and chronic kidney disease) disease.
Core Innovation
The disclosure relates to compounds of Formula I, including Formula (A) subfamilies designated as Formulas I–XIII, substituted hydroxypyrazole–pyridine scaffolds, and pharmaceutically acceptable salts thereof that inhibit PHD1, PHD2, and PHD3. The structural genus defines variable positions for X, Y, Z, A, substituents R1 through R24, m, and n, encompassing sulfonyl, sulfinyl, sulfonimidoyl, phosphine oxide, phosphonate, carbonyl, carboxyalkyl, amino, halogen, cycloalkyl, heterocycloalkyl, and heteroaryl alternatives, alongside deuterated variants and stereoisomers.
The chemical entities, including an exemplary series of Compounds 1–83 and nitrile- or chlorophenyl-substituted embodiments, effect hypoxia-inducible factor stabilization to promote tissue repair and reduce inflammation. The compounds and associated pharmaceutical compositions provide therapeutic utility for anemia and ischemic, inflammatory, cardiovascular, ocular, pulmonary, liver, renal, vascular, metabolic, and hematologic conditions, ischemia-reperfusion injury, and cancer. A TR-FRET assay measures enzyme inhibition by evaluating proline hydroxylation of HIF-1α and subsequent binding to the VHL complex.
Claims Coverage
The claims include one independent claim directed to compounds of Formula I or pharmaceutically acceptable salts thereof, comprising one inventive feature.
Formula I compound genus
Claim 1 covers a compound of Formula I, or a pharmaceutically acceptable salt thereof, with defined structural alternatives wherein X is selected from N or CR1a; Y and Z are independently selected from CH or N; A is selected from C1-3 alkyl or C3-6 cycloalkyl; m is selected from 1, 2, 3, or 4; n is selected from 0, 1, 2, or 3; and substituents R1 through R24 are selected from alkyl, cycloalkyl, halogen, amino, sulfonyl, sulfinyl, sulfonimidoyl, phosphine oxide, carbonyl-related, phosphonate, aryl, heterocycloalkyl, and heteroaryl groups.
The independent claim covers the structurally defined Formula I compound genus and pharmaceutically acceptable salts thereof across the recited structural alternatives and variable ranges.
Stated Advantages
The disclosure links PHD inhibition and HIF stabilization to potential tissue repair and reduced inflammation.
Documented Applications
Inhibition of PHD1, PHD2, and PHD3 for the treatment of PHD-mediated conditions, including anemia, ischemic, inflammatory, cardiovascular, ocular, pulmonary, liver, renal, vascular, metabolic, and hematologic diseases, ischemia-reperfusion injury, and cancer.
Pharmaceutical compositions and combination therapy comprising a claimed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
A TR-FRET assay for measuring inhibition of PHD1, PHD2, and PHD3 through HIF-1α proline hydroxylation and binding to the VHL complex.
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