Compounds and methods for inducing UCP1 expression

Inventors

Vergnes, Laurent • Reue, Karen

Assignees

University of California San Diego UCSD

Abstract

The compounds and methods of the present disclosure exhibit induce Ucp1 transcription, enhance of mitochondrial respiration, activate protein kinase A, increase lipolysis, and increase p38 MAPK phosphorylation in cells, particularly brown adipocytes and white adipocytes. They also protect primary cardiomyocytes against hypertrophy induced by adrenergic agonists. Such compounds and methods are useful in the treatment and prevention of conditions such as obesity and associated complex metabolic, endocrine, and hemodynamic changes, as well as related conditions as dyslipidemias, cardiovascular disease, and type 2 diabetes.

Core Innovation

The invention relates to small-molecule compounds of formula (Ia), including tautomers and/or salts, defined by substituent and ring-forming constraints including X being S or CH2 and R1–R8 variable groups, with a quinazolin-4-on-2-yl group at R7. The disclosed therapeutic approach uses these compounds to induce Ucp1 transcription and thermogenic programs in brown adipocytes and white adipocytes.

The document describes that the compounds increase mitochondrial respiration and activate protein kinase A (PKA). It further describes enhanced lipolysis and increased phosphorylation of p38 MAPK in brown and white adipocytes, together with protein-stabilization experiments suggesting binding to AKAP1 and AKAP13 to modulate PKA signaling.

Beyond adipocyte biology, the document describes cardioprotection by protecting cardiomyocytes from β-adrenergic-agonist-induced hypertrophy, and it reports therapeutic uses including treating or preventing obesity and associated complex metabolic, endocrine, and hemodynamic changes, dyslipidemias, cardiovascular disease, and type 2 diabetes. The disclosure also includes conjoint administration concepts with β-adrenergic agonists.

Claims Coverage

The independent claims cover three method categories: treating or preventing a condition by administering a compound of formula (Ia), conjointly administering a β-adrenergic agonist with a compound of formula (Ia), and reducing β-adrenergic agonist-induced cardiac hypertrophy by administering a compound of formula (Ia). Across these categories, the claims specify the compound identity by structural constraints using X, R1–R8, including a quinazolin-4-on-2-yl group at R7 and optional dioxane/dioxolane ring formation from R3 and R4.

Across the independent claims, the core coverage is centered on methods that administer a compound of formula (Ia), including tautomers and/or salts, defined by specific substituent and ring constraints, with therapeutic use directed to obesity and associated metabolic disorders, and with β-adrenergic-agonist-related patient treatment including conjoint administration and reduction of β-adrenergic agonist-induced cardiac hypertrophy.

Stated Advantages

Documented Applications