Spiro azepane-oxazolidinones as Kv1.3 potassium channel blockers: WO2010066840

Abstract

This article evaluates a patent application from Solvay Pharmaceuticals, which claims spiro azepaneoxazolidinones as novel blockers of the voltage-gated potassium channel Kv1.3 for the treatment of diabetes, psoriasis, obesity, transplant rejection and T-cell mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. The patent describes a new chemotype of Kv1.3 blockers and thus illustrates the growing interest of the pharmaceutical industry in Kv1.3 as a target of immunosuppression and metabolic disorders. This article briefly summarizes the chemistry and biological data provided in the patent and then compares the new compounds to Kv1.3 blockers previously disclosed by both academia and pharmaceutical companies.

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K+ channel pattern in T cells

“…PAP‐1, a synthesized compound Kv1.3 selective, suppresses allergic contact dermatitis by reducing IFN‐ γ production from T EM cells . The synthesized spiro azepone‐oxazolidinone is also considered a novel blocker of Kv1.3 channel for the treatment of diabetes, psoriasis, obesity, transplant rejection and T‐cell mediated autoimmune diseases …”

“…Recently, many important studies have shown that the T EM is associated with autoimmune diseases (e.g. rheumatoid arthritis, multiple sclerosis, lupus systemic erythematosus and type II diabetes) and that the Kv1.3 channel is up‐regulated in these cells …”

Exploring the therapeutic opportunities of potassium channels for the treatment of rheumatoid arthritis

“…After inducing the rats with diseased conditions, the results revealed that ShK-186-treated animals had significantly fewer affected joints and showed improvement in radiological and histopathological studies ( Beeton et al, 2011 ). In 2008, a company, Solvay Pharmaceuticals, filed a patent for oxazolidinediones-spiro-azepene as a novel blocker of Kv1.3 potassium channels for the treatment of T-cell-regulated autoimmune diseases such as RA ( Wulff, 2010 ). In addition, kaliotoxin is a molecule with Kv1.3 blocking activity and can be used to treat delayed-type hypersensitivity in RA patients ( Beeton et al, 2001 ; Wulff, 2010 ).…”

Small-Molecule Modulators of Mitochondrial Channels as Chemotherapeutic Agents

“…Derivatives of correolide, a pentacyclic natural compound, have been the object of a SAR study [177]. Patent applications seek to protect whole classes of synthetic K V 1.3 blockers, based on an amide [178] or an oxazolidinedione [179] core. Interestingly, PM K V 1.3 is inhibited downstream of ceramide production by acid sphingomyelinase (ASM) [180].…”