Metalloenzyme inhibitor compounds
Inventors
Hoekstra, William J. • Schotzinger, Robert J. • Rafferty, Stephen W.
Assignees
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Publication Number
US-11247981-B2
Publication Date
2022-02-15
Expiration Date
Abstract
The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
Core Innovation
The invention relates to a method of treating a subject suffering from or susceptible to a disorder or disease by administering an effective amount of a compound of Formula I, or a salt thereof, where MBG is tetrazolyl and the substituents R1, R2, R3, R4, R5, R6 and n are constrained within defined chemical options. In Formula I, R1 and R2 are halo; R3 is independently halo, haloalkoxy, haloalkoxyalkyl, or hydroxyl; R4 is aryl optionally substituted with 0, 1, 2 or 3 independent R3; R5 is H or —P(O)(OH)2; R6 is H or halo; and n is 0, 1, 2 or 3.
The disclosure frames the invention around metalloenzyme modulation and inhibition using metal-binding groups intended to balance potency and selectivity while reducing off-target toxicity. The background discusses metal-binding moieties such as azoles that bind heme iron in CYP51 and may also bind off-target CYP enzymes, and hydroxamate metal-binding behavior that may involve off-target zinc binding.
The patent further describes therapeutic composition embodiments and disease-relevant targeting, including metalloenzymes such as CYP51 (lanosterol demethylase) and other metalloenzyme families including matrix metalloproteases, histone deacetylases, carbonic anhydrases, and additional listed enzyme targets. The document includes exemplary treatment contexts and selectivity examples for Candida albicans versus CYP2C9, CYP2C19, and CYP3A4, and it also lists pathogenic fungi and disease/organism contexts for which the Formula I compounds are used.
Claims Coverage
The independent claim in the provided set covers a method of treating a subject using an effective amount of a Formula I compound (or a salt) with core structural constraints on MBG and substituents, including a defined set of allowable groups for R1–R6 and the value range for n. Dependent claims refine the substituent choices and associate the method with specified pathogenic fungi and named compound embodiments.
Formula I method of treatment with constrained MBG and substituents
A method of treating a subject suffering from or susceptible to a disorder or disease by administering an effective amount of a compound of Formula I, or salt thereof, wherein MBG is tetrazolyl; R1 is halo; R2 is halo; R3 is independently halo, haloalkoxy, haloalkoxyalkyl, or hydroxyl; R4 is aryl, optionally substituted with 0, 1, 2 or 3 independent R3; R5 is H or —P(O)(OH)2; R6 is H or halo; and n is 0, 1, 2 or 3.
Pathogenic fungi-associated treatment refinement
The method further specifies that the disorder or disease is associated with one or more enumerated pathogenic fungi.
Haloalkoxy or haloalkoxyalkyl R3 with n fixed to 1
The method further specifies that R3 is haloalkoxyalkyl or haloalkoxy and n is 1.
R3 as 2,2,2-trifluoroethoxy with n fixed to 1
The method further limits R3 to 2,2,2-trifluoroethoxy and fixes n to 1.
R4 as a phenyl group substituted with 2 fluoro
The method further specifies that R4 is a phenyl group substituted with 2 fluoro.
Specific Formula I compound and dihydrogen phosphate salt embodiment
The method is carried out using a specific compound embodiment of Formula I or a dihydrogen phosphate form.
Overall, the claim coverage is centered on administering an effective amount of a Formula I compound or salt where MBG is tetrazolyl and the substituent framework is explicitly constrained, with dependent claims narrowing R3 and n, specifying R4 as a fluoro-substituted phenyl pattern, optionally associating the treatment with enumerated pathogenic fungi, and optionally specifying named Formula I embodiments including a dihydrogen phosphate salt.
Stated Advantages
Balance potency/selectivity and reduce off-target toxicity.
Improved selectivity is supported by selectivity examples comparing Candida albicans MIC values versus CYP2C9, CYP2C19, and CYP3A4 IC50.
Documented Applications
A method of treating a subject suffering from or susceptible to a disorder or disease by administering an effective amount of a Formula I compound or salt thereof.
The disorder or disease is associated with one or more enumerated pathogenic fungi, including Candida albicans, Aspergillus niger, Cryptococcus neoformans, Trichophyton rubrum, and Pneumocystis carinii.
Methods for treating a subject suffering from or susceptible to a disorder or disease by administering Formula I compounds, including disorders or diseases associated with specified pathogenic fungi (e.g., Candida albicans and many other listed fungi).
Antifungal MIC testing against Candida albicans, including a MIC rating scale (Example 59).
Selectivity/metalloenzyme assay results reported as IC50 values for CYP2C9, CYP2C19, and CYP3A4, with fluconazole and voriconazole controls (Example 60).
Analytical characterization of Formula I example compounds using HPLC/ESI-MS retention times and m/z data for Example Compounds 28-58 (Table 2 context).
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