Quinolines that modulate SERCA and their use for treating disease

Inventors

Dahl, Russell

Assignees

Neurodon Corp

Abstract

Provided herein are compounds of Formula I, pharmaceutical compositions thereof, and methods of their use for treating, preventing, or ameliorating one or more symptoms of a neurological disease, neurodegenerative disorder, or diabetes.

Core Innovation

The invention relates to SERCA-targeting small-molecule compounds, including quinolines having a structural formula and related variable structures, as SERCA agonists and allosteric modulators. The disclosure links SERCA modulation to endoplasmic reticulum stress biology, reduced ER stress, and improved ER Ca2+ homeostasis through modulation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase activity, including modulation of SERCA2b.

The disclosed compound set includes pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, isotopic variants, and related chemical families identified as E1–E4, F1–F4, G1–G8, and H1–H11, together with example compound embodiments labeled A1–A14. The description also states that the compounds can act across SERCA isoforms including SERCA2a, SERCA1, and SERCA3, and connects this SERCA-mediated mechanism to downstream ER stress signaling elements including PERK, eIF2α, and C/EBP homologous protein (CHOP).

The document further describes pharmaceutical compositions comprising a therapeutically effective amount of a compound of the structural formula, or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier, excipient or diluent. The overall disclosure links treatment to restoring ER homeostasis, increasing ER Ca2+ concentration, cell rescue under ER-stress conditions, and disease contexts such as diabetes, hepatosteatosis, obesity, Alzheimer’s disease, and Parkinson’s disease.

The disclosure further emphasizes pharmacokinetic improvements for specific SERCA modulators, including examples with C18–C20 compared with earlier Formula I analogs, while maintaining the ER stress and ER Ca2+ homeostasis rationale. The description includes a generic Scheme I/Scheme Ia concept for chemical construction and reports biological outcomes including glucose lowering, glucose tolerance effects, Alzheimer’s plaque/memory effects, and dyskinesia in a 6-OHDA-lesioned model.

Claims Coverage

The provided claim content covers one independent pharmaceutical-composition claim and several dependent treatment claims. The inventive coverage centers on a therapeutically effective amount of a specified SERCA-targeting structural-formula compound, or a pharmaceutically acceptable salt, formulated with a pharmaceutically acceptable carrier, excipient or diluent, with treatment narrowed to diabetes, type 1 diabetes, type 2 diabetes, and Alzheimer’s disease.

Overall, the claim set provided is directed to compositions of a specified structural-formula SERCA-targeting compound, or salt, formulated with pharmaceutically acceptable carriers, where administration is used to treat diabetes, type 1 diabetes, type 2 diabetes, and Alzheimer’s disease.

Stated Advantages

Documented Applications