Metalloenzyme inhibitor compounds
Inventors
Sparks, Steven • Yates, Christopher M. • Shaver, Sammy R. • Hoekstra, William J.
Assignees
Corxel Pharmaceuticals Hong Kong Ltd • Mycovia Pharmaceuticals Inc
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Publication Number
US-11040034-B2
Publication Date
2021-06-22
Expiration Date
Abstract
Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
Core Innovation
The disclosure relates to structurally defined small-molecule compounds, including Formula I pyridazine-containing compounds and substituted benzimidazole and pyridazinyl derivatives, with broad substituent definitions and multiple example compounds. The compounds are described as capable of binding metals via a pyridazine moiety and as showing metalloenzyme affinity, including potent CYP11B2 inhibition with selectivity over CYP11B1.
The document also describes prodrugs, prodrug moieties, in situ esterification or activation, salts, stereoisomers, tautomers, polymorphs, and extended-release formulations. It further includes synthetic preparation, reaction schemes, intermediates, and characterization by NMR, LC-MS, HPLC, and LC-MS/HPLC, together with explicit structural and stereochemical conventions.
Therapeutic use is described in methods of treatment for metalloenzyme-mediated disorders and hypertension-related disorders, including resistant hypertension. The compounds are framed for administration to a subject or patient to modulate metalloenzyme activity and inhibit aldosterone synthase (CYP11B2) activity, with comparative language indicating reduced undesired CYP11B1 activity and improved metabolic stability versus pyridine counterparts.
Claims Coverage
The consolidated claim coverage centers on three inventive features: administering structurally selected compounds to alleviate or abate hypertension, inhibiting aldosterone synthase (CYP11B2) activity in a patient with hypertension by contacting structurally selected compounds with CYP11B2, and treating resistant hypertension as a dependent refinement.
Administering structurally selected compounds for hypertension treatment
A method of alleviating or abating hypertension, or ameliorating a symptom thereof, in a patient by administering an effective amount of a compound having a structure selected from a specified group.
Inhibiting aldosterone synthase (CYP11B2) activity by contacting structurally selected compounds
A method of inhibiting aldosterone synthase (CYP11B2) activity in a patient with hypertension by contacting a compound having a structure selected from a specified group with aldosterone synthase (CYP11B2).
Treating resistant hypertension
The method wherein the hypertension is resistant hypertension.
Overall, the independent claims are directed to patient treatment using structurally selected compounds, with one claim focused on hypertension relief and the other on CYP11B2 inhibition in hypertensive patients. The provided text also includes resistant hypertension as a dependent refinement.
Stated Advantages
Selectively inhibit aldosterone synthase (CYP11B2) to avoid off-target aldosterone accumulation.
Avoid CYP11B1 cortisol suppression.
Treat hypertension-related disorders, including resistant hypertension, via metalloenzyme-mediated activity modulation.
Potent CYP11B2 inhibition with selectivity over CYP11B1.
Pyridazine analogs reduce CYP11B1 inhibition compared to pyridine analog replacements, which increase CYP11B1 inhibition and reduce selectivity.
Improved metabolic stability versus pyridine counterparts.
Performance versus known CYP11B2 inhibitors characterized by reduced undesired CYP11B1 activity.
Alleviating or abating hypertension or ameliorating a symptom thereof in a patient.
Inhibiting aldosterone synthase (CYP11B2) activity in a patient with hypertension.
Documented Applications
Treating hypertension or alleviating or abating a symptom thereof in a patient, including resistant hypertension.
Inhibiting aldosterone synthase (CYP11B2) activity in a patient with hypertension.
Treating metalloenzyme-related disorders through administration of Formula I compounds.
Methods of treatment for metalloenzyme-mediated disorders, including hypertension and resistant hypertension, by administering Formula I compounds.
Pharmaceutical compositions, salts, kits, and extended-release formulations for use with Formula I compounds, as described in the document.
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