LXR modulators with bicyclic core moiety
Inventors
Gege, Christian • Kinzel, Olaf • Hambruch, Eva • Birkel, Manfred • Kremoser, Claus • Deuschle, Ulrich
Assignees
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Publication Number
US-11618747-B2
Publication Date
2023-04-04
Expiration Date
Abstract
The present invention relates to bicyclic compounds (e.g. indoles) containing a sulfonyl moiety, which bind to the liver X receptor (LXRα and/or LXKβ) and act preferably as inverse agonists of LXR.
Core Innovation
The invention relates to a compound represented by Formula (I), optionally as a glycine conjugate, tauro conjugate, enantiomer, diastereomer, tautomer, N-oxide, solvate, prodrug, or pharmaceutically acceptable salt. The compound includes an annelated 5- to 6-membered cycle forming a 6-membered aryl or a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, with extensive substitution patterns and optional additional ring formation.
Formula (I) further allows optionally two adjacent substituents on the aryl or heteroaryl moiety to form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S, or N. Optionally two adjacent substituents on the cycloalkyl or heterocycloalkyl moiety form a 5- to 6-membered unsaturated cycle, and the structure is further defined by a linker L, variable substituent groups, and 1,2-orientation regarding the connection or an annelated additional cycle in 1,2-orientation.
The framework is described as a broad Formula (I) scaffold with selected aryl, heteroaryl, cycloalkyl, and heterocycloalkyl ring-size ranges and substitution options, including halogen, CN, SF5, NO2, oxo, hydroxy, CO2H, alkoxy, sulfonyl, amide, and carbonyl-related motifs. In the provided biological context, the document evaluates compounds for LXR inverse-agonist activity, reports oral bioavailability and higher liver-to-plasma exposure, and describes hepatic target gene suppression in a short-term high-fat-diet mouse study.
Claims Coverage
The independent claim coverage centers on one Formula (I) compound genus with multiple inventive features, including an annelated aryl/heteroaryl cycle, optional additional partially unsaturated cycles, a defined linker L, and optional conjugate and salt forms. Four main inventive features are consistently reflected across the input items.
Formula (i) compound with optional conjugate and salt forms
A compound represented by Formula (I) optionally as a glycine conjugate, tauro conjugate, enantiomer, diastereomer, tautomer, N-oxide, solvate, prodrug, or pharmaceutically acceptable salt thereof.
Annelated aryl/heteroaryl core with defined heteroatom content
An annelated 5- to 6-membered cycle forming a 6-membered aryl or a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, with specified substitution limits.
Optional adjacent-substituent ring formation
Optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, and optionally two adjacent substituents on the cycloalkyl or heterocycloalkyl moiety form a 5- to 6-membered unsaturated cycle.
Defined linker L and 1,2-orientation constraint
L is selected from a bond, alkylene, alkenylene, alkinylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene classes with specified substitution options, and the structure includes a 1,2-orientation feature regarding the connection or an annelated additional cycle in 1,2-orientation.
Across the provided items, the claims define a broad Formula (I) scaffold with an annelated aryl/heteroaryl ring system, optional additional partially unsaturated cycles, a defined linker L, and explicit coverage of glycine/tauro conjugate and related pharmaceutically acceptable forms.
Stated Advantages
Orally bioavailable invention compounds.
Higher liver-to-plasma exposure for invention compounds.
Effective hepatic target gene suppression in a short-term high-fat-diet liver study.
Documented Applications
Evaluation as LXR inverse agonists using TR-FRETβ ligand-binding assay and LXR Gal4 mammalian two-hybrid transient transfection assays.
In vivo hepatic target gene suppression study in a short-term high-fat-diet mouse model, including suppression of Scd1, Fas, and Srebp1c.
Medicaments for treating diseases mediated by LXR modulators, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, metabolic disorders, familial hypercholesterolemia, metabolic syndrome, obesity, insulin resistance, type II diabetes, cancer, viral myocarditis, and hepatitis C virus infection.
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