Cell metabolism modulating compounds and uses thereof
Inventors
Assignees
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Publication Number
US-12084419-B2
Publication Date
2024-09-10
Expiration Date
Abstract
A novel class of compounds according to Formula I, II, or III, wherein W1-W4, Z1-Z4, Z1-Z5, X, Y, n, and R1-R8 are as defined in the claims and description of embodiments that bind to fatty acid binding protein FABP4 and modulate adipocyte metabolism to drive enhanced glucose utilization, as well as pharmaceutical compositions comprising the class of compounds, in combination with a pharmaceutically acceptable diluent or carrier, and optionally, further in combination with a therapeutically active agent, and the use of these compounds in medicine and for the preparation of a medicament in the treatment of disorders acting on the FABP4. In examples, the ring Z contains Z1-Z4. In other examples, the ring Z contains Z1-Z5.
Core Innovation
The invention relates to compounds defined by Formula I, Formula II, and Formula III, as well as specific members selected from a group of substituted cyclohepta[b]indole-4-carboxylic acids and related fused indole/carbazole carboxylic acids. The compounds include ring substituents W and Z with independently selected heteroatoms and substituent groups R1, R2, R7, and variable groups denoted by n and by R3, R4, R5, R8, or R6, with an acid isostere option. The structural definitions include allowed functional groups such as CN, OH, COOH, OCH3, CF3, CONH2, B(OH)2, B(OR)2, and pharmaceutically acceptable salts or stereoisomers.
The document further provides specific compound selections and stereochemical refinements, including a group of named substituted cyclohepta[b]indole-4-carboxylic acids and related tetrahydro-1H-carbazole-8-carboxylic acids. A dependent refinement specifies that the selected compound is a pure optical isomer.
The compounds are intended to bind fatty acid binding protein FABP4 (aP2) and thereby modulate adipocyte metabolism, with this modulation linked to enhanced glucose utilization. The document also reports characterization and analytics for multiple substituted cyclohepta[b]indole/carbazole carboxylic acid derivatives, including 1H NMR, mass/HRMS, and reversed-phase HPLC/UPLC characterization methods designated Methods A-F.
Claims Coverage
The provided independent claims include four compound-defining claim sets: a Formula I scaffold, a Formula II scaffold, a Formula III scaffold, and a specific selected group of substituted cyclohepta[b]indole-4-carboxylic acids and related fused indole/carbazole carboxylic acids. The inventive features are the structured compound scaffolds, the allowed substituent selections, the acid isostere and stereoisomer options, and the selected compound group.
Formula I compound scaffold
A compound of Formula I comprising W and Z with each independently selected from C, CH, O, S, or N; X is independently CH2, N or CHR4; Y is independently CH2 or CHR5; n is between 0 and 3; substituents R1 on ring Z and R2 on ring W are selected from CN, OH, COOH, OCH3, CF3, CONH2, B(OH)2, B(OR)2, acid isostere, halogen, substituted or unsubstituted cyclic or heterocyclic options, and SO2NH2; R7 is hydrogen or one of the specified groups; and R3/R4/R5/R8/R6 are each independently selected from hydrogen, an alkyl or ether having 2 to 12 carbon atoms, a substituted amine, or (CH2)mG with defined m and G options, with pharmaceutically acceptable salts or stereoisomers thereof.
Formula II compound scaffold with restricted substituents
A compound of Formula II with n equal to 0, 1, or 2; R1 selected from CN, COOH, CONH2, B(OH)2, B(OR)2, acid isostere, and a halogen not being a fluoro substituent; R2 selected from CN, COOH, CONH2, B(OH)2, B(OR)2, acid isostere, a halogen, and a bicyclic heteroaryl; R7 is hydrogen or one of the specified groups; and R3, R4, R5, R8, or R6 are independently hydrogen, alkyl having 1 to 12 carbon atoms, or (CH2)mG with m between 1 and 12 and G selected from cycloalkyl containing 3 to 6 carbon atoms, phenyl, or CF3/CF2H/CFH2, with pharmaceutically acceptable salts included.
Formula III compound scaffold
A compound of Formula III with n equal to 0, 1, or 2; R1 and R2 each independently selected from CN, COOH or CONH2; and R3 independently selected from alkyl having 1 to 12 carbon atoms or (CH2)mG where G is independently selected from cycloalkyl containing 3 to 6 carbon atoms or phenyl, with pharmaceutically acceptable salts thereof.
Selected substituted cyclohepta[b]indole-4-carboxylic acids and related fused carboxylic acids
A compound selected from named substituted cyclohepta[b]indole-4-carboxylic acids and related fused indole/carbazole carboxylic acids, including pharmaceutically acceptable salts or stereoisomers thereof.
Across the independent claims, the coverage is centered on compound classes defined by Formula I, Formula II, and Formula III with extensive structural substituent limitations, plus a selected group of substituted cyclohepta[b]indole and related fused indole/carbazole carboxylic acids. The claim set defines the compound structures themselves, with dependent refinement to pure optical isomers.
Stated Advantages
Enhancing glucose utilization.
Modulating adipocyte metabolism.
Inhibiting FABP4.
Documented Applications
Treatment or prophylaxis for disorders acting on FABP4, including type-2 diabetes, obesity, cardiovascular disease, asthma, cancer, and other inflammatory/metabolic disorders.
Pharmaceutical composition and medicament use for administration, together with methods of inhibiting FABP4 and manufacturing medicaments.
Characterization of substituted cyclohepta[b]indole/carbazole carboxylic acid derivatives using 1H NMR, mass/HRMS, and reversed-phase HPLC/UPLC, including correlation of IUPAC names with HPLC retention times and molecular weights.
Biological evaluation of compounds by measuring glucose consumption in differentiated 3T3-L1 adipocytes.
Biological evaluation of FABP4 inhibition using a Terbium-based TR-FRET assay.
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