Methods and agents for treating disease
Inventors
Panicker, Bijoy • Oehlen, Lambertus J. W. M.
Assignees
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Publication Number
US-11434234-B2
Publication Date
2022-09-06
Expiration Date
Abstract
The present invention provides compounds having the general structural formula (I) and pharmaceutically acceptable derivatives thereof, as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases involving elevated levels of aldosterone or abnormal or excessive fibrosis, such as kidney disease and hypertension.
Core Innovation
The invention relates to aldosterone-suppressing/antifibrotic small-molecule compounds defined as compounds of Formula (I), including derivatives, salts, enantiomers, stereoisomers, polymorphs, and solvates. The variability of the structures is defined by substituents R1-R4 and R2-R9, with each substituent selected from extensive groups and optional substitutions via R7. In the described embodiments, R4 is OH.
The problem addressed is the effect of elevated aldosterone and fibrosis across multiple diseases, including chronic kidney disease (CKD) and hypertension, and fibrosis in the liver, lung, and heart, as well as kidney-related conditions. The disclosure frames aldosterone breakthrough and the progression of fibrosis as linked to the renin-angiotensin-aldosterone system (RAAS) and presents the compounds as inhibiting aldosterone synthase (CYP11B2), with selectivity over CYP11B1 in certain embodiments.
The compounds are also disclosed in the context of pharmaceutical compositions for administration. The disclosure includes disease-targeting and assessment in vitro and in vivo, including CYP11B1 versus CYP11B2 inhibition and multiple fibrosis- and injury-related models such as kidney injury/renal dysfunction, unilateral ureteral obstruction (UUO), 5/6 nephrectomy, ARPKD, and liver and lung fibrosis, as well as cerebral infarction/stroke models. The disclosure reports example activity data with histological and functional endpoints to support aldosterone suppression and antifibrotic effects.
Claims Coverage
The document contains one independent claim directed to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, defining inventive structural constraints through variable substituents R1-R8/R9 and optional substitutions via R7, with R4 fixed as OH. Dependent claims further refine the scope by enumerating specific allowable substituents and adding relationship constraints among substituent positions, and by defining a pharmaceutical composition.
Formula (I) compound with defined substituent variability and R4 is OH
A compound as described in Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3 are defined by specific allowable groups; R4 is OH; R5 and R6 are defined by specific allowable groups; R7 provides optional substitutions; and R8 and R9 are defined by specific allowable groups and relationships for each of R8 and R9.
Pharmaceutical composition comprising the Formula (I) compound
A pharmaceutical composition including the compound as described in Formula (I) together with a pharmaceutically acceptable carrier, diluent, or excipient.
Overall, the independent claim covers aldosterone-suppressing/antifibrotic compounds defined by Formula (I) with R4 fixed as OH and broad allowable substituent choices governed by R1-R3, R5-R7, and R8-R9. Dependent claims narrow the scope by specifying particular substituent choices, and by imposing structural relationship constraints among substituent positions, and also include pharmaceutical compositions.
Stated Advantages
Inhibits aldosterone synthase (CYP11B2) with selectivity over CYP11B1 in certain embodiments.
Aldosterone-suppressing and antifibrotic effects are supported across fibrosis- and injury-related disease models described in the disclosure.
Documented Applications
Chronic kidney disease (CKD).
Hypertension.
Liver fibrosis, pulmonary fibrosis, and cardiac fibrosis.
Renal fibrosis and kidney injury/renal dysfunction in kidney-related models.
Unilateral ureteral obstruction (UUO) model.
5/6 nephrectomy model.
Polycystic kidney disease / ARPKD model.
Bleomycin-induced lung fibrosis model.
Scleroderma/systemic sclerosis fibrosis context.
Hepatic stellate cells (LX2) context.
Cerebral infarction/stroke model, including middle cerebral artery occlusion (MCAO).
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