GLP-1R agonists and uses thereof
Inventors
Assignees
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Publication Number
US-11591321-B2
Publication Date
2023-02-28
Expiration Date
Abstract
The present disclosure provides compounds of Formula (III)and pharmaceutical compositions thereof, for use in, e.g. treating type 2 diabetes mellitus, pre-diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease.
Core Innovation
The invention relates to compounds represented by structural formula (III), including pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates. The structural definition uses X1, X2, X3, X4, and X5 at defined positions, where each is independently selected from N and CH, with a limitation that no more than three of X1, X2, X3, X4, and X5 are N. Ring A is constrained such that it does not contain 3 nitrogen ring atoms at 3 contiguous positions.
Ring B is defined as a 6 membered heteroaryl or phenyl system in which Y1, Y3, Y4, and Y5 are each independently selected from N or CH, with no more than 3 nitrogen ring atoms in ring B and no 3 nitrogen ring atoms at 3 contiguous positions. Additional ring-system constraints are defined by T6, T7, and T8 each independently selected from N and CR4. The invention further constrains EE to be —COOH or a carboxylic group surrogate, with substituent-variable classes for R1, R2, R3, R4, R5′, and R6′ and integer variables m, n, and o selected from specified ranges.
The disclosed scaffold tightly controls heteroatom patterns, functional-group placement, substituent classes, and stereochemical and solid-form variants of structural formula (III). The partial content also describes a biased pharmacology concept in which the disclosed compounds function as full agonists for GLP-1R-mediated cAMP signaling while being partial agonists for β-arrestin recruitment/internalization relative to GLP-1, directed to sustained cAMP signaling with reduced GI side effects and improved tolerability.
Claims Coverage
The independent claim covers a structurally defined compound of structural formula (III) and its pharmaceutically acceptable forms, with coordinated restrictions on ring A, ring B, EE, T6–T8, and the substituent classes for R1–R6′ plus integer variables m, n, and o. The claim is further described in the context of GLP-1R agonist compounds.
Structural formula (III) compound with pharmaceutically acceptable forms
A compound represented by structural formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.
Ring A nitrogen contiguity and X1–X5 composition limits
X1, X2, X3, X4, and X5 are each independently selected from N and CH, no more than three of X1–X5 are N, and ring A does not contain 3 nitrogen ring atoms at 3 contiguous positions.
Ring B heteroaryl/phenyl definition with nitrogen contiguity and atom limits
Ring B is a 6 membered heteroaryl or phenyl where Y1, Y3, Y4, and Y5 are each independently selected from N or CH, there are no more than 3 nitrogen ring atoms in ring B, and ring B does not contain 3 nitrogen ring atoms at 3 contiguous positions.
EE as —COOH or a carboxylic group surrogate
EE is —COOH or a carboxylic group surrogate, optionally defined by a surrogate that is Rb, with Rb selected from hydrogen, specified C1–C6 alkyl/alkoxy classes, NR5′R6′, and specified aryl/heteroaryl/cycloalkyl/heterocyclyl classes, each with defined optional substituent selections.
T6–T8 heteroatom/CR4 limitation
T6, T7, and T8 are each independently selected from N and CR4.
Constrained substituent classes and integer variables
Each R1, R2, R3, and R4 is independently selected from the defined substituent classes with optional substitutions; R5′ and R6′ are each independently selected from hydrogen and C1–C6 alkyl; and integers m, n, and o are each selected from 0, 1, 2, 3, and 4.
Overall, the independent claim covers a GLP-1R agonist compound of structural formula (III) with tightly restricted ring A and ring B nitrogen/contiguity patterns, defined heteroatom selections for T6–T8, EE as —COOH or a carboxylic group surrogate, and extensive constrained substituent classes and integer variables m, n, and o, together with pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate forms.
Stated Advantages
Reduced GI side effects relative to GLP-1.
Improved tolerability.
Sustained cAMP signaling.
Documented Applications
Therapeutic use for cardiometabolic diseases including Type 2 diabetes mellitus and pre-diabetes, obesity, NASH/NAFLD, and cardiovascular diseases via GLP-1R-mediated cAMP signaling enhancement.
A method for treating a subject in need by administering a therapeutically effective amount of the disclosed compound for diseases including various diabetes states, hyperglycemia and insulin resistance conditions, cardiometabolic vascular and heart diseases, hepatic disorders, obesity-related conditions, and other listed conditions.
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