PPAR-sparing compounds for the treatment of metabolic diseases
Inventors
Tanis, Steven P. • Larsen, Scott D. • Artman, III, Gerald D. • Parker, Timothy
Assignees
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Publication Number
US-9562012-B2
Publication Date
2017-02-07
Expiration Date
Abstract
The present invention relates to hydroxamate compounds and pharmaceutical compositions that are useful for treating and/or preventing metabolic inflammation mediated diseases such as diabetes, obesity, hypertension, dyslipidemia, a neurodegenerative disorder (e.g., Alzheimer's disease, Parkinson's disease, or Huntington's disease), or any combination thereof. Moreover, the present invention also provides methods of treatment for these diseases or disorders.
Core Innovation
The invention relates to a compound of Formula II, or a pharmaceutically acceptable salt thereof, defined by extensive substituent definitions for R1, R2, R3, R4, R5, R6, and R7, together with a defined Ring A. R1 and R2 are independently selected from a specified set of groups, with an option that R1 and R2 together form an optionally substituted heterocyclic ring that includes an N atom and an O atom and up to one additional heteroatom selected from N, O, or S. Ring A is a 5-8 membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms selected from N, O, or S, and Ring A is optionally substituted with R6.
The defined structure further includes R3 as a C1-6 alkyl group optionally substituted with halo, OH, or phenyl. R4 and R5 are independently selected from a range of hydrogen-bonding and carbonyl/heteroatom-containing substituents, or R4 and R5 together form oxo or an N–O–R7 group. Each R6 is selected from halo, H, CN, OR7, NO2, C1-6 alkyl, aryl, heteroaryl, S(O)2R7, or C(O)R7, each optionally substituted with halo or OH; each R7 is independently H, C1-6 alkyl, C3-8 cycloalkyl, or phenyl. The combination of these selectable substituent patterns defines a chemical space for Formula II compounds.
The document describes hydroxamate PPARγ-sparing compounds and related scaffold formulas, including Formula I and Formula II and named variants such as Formula IIa and Formula IIb. The disclosed compounds are presented in relation to reduced PPARγ binding and activation, and pharmaceutically acceptable salts are included within the scope of the disclosed compounds. The disclosure also frames the compounds in relation to beta-adrenergic receptor β21/β22/β23 and PPARγ3β interaction.
Claims Coverage
Two independent claim sets are identified in the provided claims list. One independent claim covers a broad structural genus defined by Formula II substituent options and a defined Ring A; the other independent claim covers a specific selection of numbered compounds. The inventive features are primarily structural, with one dependent claim also covering a pharmaceutical composition including the compound.
Formula II compound (or pharmaceutically acceptable salt)
A compound of Formula II, or a pharmaceutically acceptable salt thereof, where R1 and R2 are independently selected from specified substituent groups or together form an optionally substituted heterocyclic ring including an N atom and an O atom; R3 is a C1-6 alkyl group optionally substituted with halo, OH, or phenyl; R4 and R5 are independently selected from specified substituent groups or together form oxo or an N–O–R7 group; Ring A is a 5-8 membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms selected from N, O, or S and is optionally substituted with 1-3 groups of R6; each R6 and R7 are selected from the defined sets of substituents.
Selected numbered compounds
A compound selected from the listed compound structures identified as Compound 2, Compound 8, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20, and Compound 21.
The claim coverage is structural: one independent claim defines a wide Formula II scaffold with detailed substituent and Ring A constraints, while the other independent claim identifies a set of specific numbered compounds. The provided dependent coverage also narrows the genus to specific sub-structures and includes a pharmaceutical composition claim.
Stated Advantages
Reduced PPARγ activation.
Avoiding sodium reabsorption, fluid retention, and weight gain associated with PPARγ-activating thiazolidinediones.
Promoting brown adipose tissue differentiation while increasing UCP1 protein.
Delaying the onset of metabolic mediated diseases including diabetes, obesity, and dyslipidemia.
Documented Applications
Therapeutic applications for metabolic and neurodegenerative diseases, including Alzheimer’s disease biomarkers (CSF Aβ, CSF AT) and ADAS cognitive testing, and Parkinson’s disease unified PD rating scale with time to emergence and time to dopaminergic therapy, as well as diabetes/obesity-related conditions.
Biological evaluation of Formula I compounds for PPARγ activity using a TR-FRET competitive binding assay and a GeneBLAzer cell reporter assay, including additional functional/binding readouts reported in Table 2.
Treating metabolic mediated disorders, including diabetes mellitus, obesity, dyslipidemia, and hypertension.
Neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.
Use in the context of delaying the onset of metabolic mediated diseases including diabetes, obesity, and dyslipidemia, and involving PPARγ3β interaction.
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