Compositions and methods for the treatment of metabolic and liver disorders
Inventors
Lian, Brian • Barker, Geoffrey E. • Barnes, Maureen • Yagiz, Kader • Stevens, Erland
Assignees
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Publication Number
US-11744873-B2
Publication Date
2023-09-05
Expiration Date
Abstract
Disclosed herein are small molecule GIP/GLP-1 dual receptor agonist compositions, pharmaceutical compositions, the use and preparation thereof.
Core Innovation
The invention relates to small-molecule GIP/GLP-1 dual receptor agonists and compounds having the structure of formula I-a, I-b, or I-c, or pharmaceutically acceptable salts thereof. The compounds are described as non-macrocyclic, non-functionalized peptides having defined variable substituent regions, including R1, R2, X and Y, R4/R5/R6, and Z1/Z2, with the proviso that at least one of Z1 and Z2 is not hydrogen.
The disclosure defines substituent options at X and Y, R4, R5, R6, Z1, and Z2, and provides stereochemical definitions for a chiral carbon marked with an asterisk (*) as either S configuration or R configuration. The compounds are further described to include stereoisomers, tautomers/resonance forms, solvates, and pharmaceutically acceptable salts of the defined structures.
The disclosure further describes pharmaceutical composition embodiments comprising the compound and pharmaceutically acceptable excipients, and therapeutic methods for preventing or treating fatty liver diseases. The described disease scope includes non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), steatosis, fibrosis, and broader metabolic disorders, including metabolic syndrome-related conditions.
Claims Coverage
The claim coverage centers on one independent compound claim directed to formula I-a, I-b, or I-c, or a pharmaceutically acceptable salt thereof. The claim set also includes a pharmaceutical composition embodiment and refined limitations on stereochemistry and substituent options.
Formula I-a/I-b/I-c compound scaffold
A compound having the structure of formula I-a, I-b, or I-c, or a pharmaceutically acceptable salt thereof, wherein X and Y each are independently selected from —OR, —NR5R6, C1-6 alkyl and haloC1-6 alkyl; each R4 is independently selected from hydrogen, C1-6 alkyl, haloC1-6 alkyl, C6-10 aryloxy and C6-10 aryl alkoxy; each R5 is hydrogen or C1-6 alkyl; each R6 is hydrogen or C1-6 alkyl; Z1 is selected from hydrogen, C1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkoxy, C3-10 cycloalkyl and C6-10 aryl; and Z2 is selected from hydrogen, C1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkoxy, C3-10 cycloalkyl and C6-10 aryl.
Selected alternative structure from a specified group
The compound has a structure selected from a specified group of alternative structures, including pharmaceutically acceptable salts thereof.
Stereochemical constraint to S configuration at chiral carbon (*)
Any chiral carbon marked with an asterisk (*) has an S configuration.
Stereochemical constraint to R configuration at chiral carbon (*)
Any chiral carbon marked with an asterisk (*) has an R configuration.
Pharmaceutical composition with therapeutically effective amount and excipient
A pharmaceutical composition comprising a therapeutically effective amount of the compound together with a pharmaceutically acceptable excipient.
Overall, the claims cover the formula I-a/I-b/I-c compound scaffold with explicitly defined allowable substituent groups at X/Y, R4/R5/R6, and Z1/Z2, optional pharmaceutically acceptable salts, selected alternative structures, and chiral carbon (*) stereochemistry constrained to S or R. The claim set also includes pharmaceutical compositions containing a therapeutically effective amount with a pharmaceutically acceptable excipient.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Preventing or treating fatty liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), steatosis.
Preventing or treating fibrosis and broader fibrosis/metabolic disorders, including conditions described as metabolic syndrome-related.
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