Potential Treatment for Neuropsychiatry Disorders with TRPC5 Modulators

Abstract

Patent Application Title: Quinazoline-2,4(1H,3H)-dione Derivatives as TRPC5 Modulators for the Treatment of Neuropsychiatry Disorders Patent Application Number: WO 2016/023826 Al Publication date: 18 February 2016 Priority Application: US 62/035,578 Priority date: 11 August 2014 Inventors: Chenard, B. L.; Gallaschun, R. J. Applicants: Hydra Biosciences, Inc.; 45 Moulton Street, Cambridge, MA, 02138, USA Boehringer Ingelheim International Gmbh; Binger Strasse 173, 55216 Ingelheim am Rhein (DE) Disease Area: Neuropsychiatry Disorders Biological Target: Short transient receptor potential channel 5 (TRPC5) Summary: The invention in this patent application relates to novel quinazoline-2,4(1H,3H)-dione derivatives. These compounds are TRPC5 modulators and may be used as medication for the treatment of conditions such as neuropsychiatric disorder, neurodegenerative disorder, nephropathy, and seizure disorder. Ion channel proteins mediate the ion flux across cellular membranes. Their proper expressions and functions are important for the maintenance of cell function as well as intracellular communications. Ion channels are important in modulating membrane potential and ion flux in cells. The misregulation of membrane potential and aberrant calcium handling are implicated in the pathogenesis of numerous diseases. Therefore, compounds that can either promote or inhibit particular ion channels are of great interest and may potentially provide therapy for different diseases. The short transient receptor potential channel 5 (TRPC5) is one of seven mammalian transient receptor potential channel proteins. TRPC5 is a multipass cation channel membrane protein that modulates the flux of calcium and sodium ions across cellular membranes. The influx of sodium and calcium leads to a depolarization of the cell, which in turn increases the probability that voltage-gated ion channels will reach the threshold required for activation. Thus, activation of nonselective cation channels can increase electrical excitability and the frequency of several voltage-dependent events including, but not limited to, neuronal action potentials, cardiac action potentials, smooth muscle contraction, cardiac muscle contraction, and skeletal muscle contraction. In addition, the activation of nonselective cation channels such as TRPC5 causes calcium influx and alters the intracellular free calcium concentrations. This has profound effects on signal transduction, gene expression, and cellular phenotype. Gene expression events include, but are not limited to, production of mRNAs encoding cell surface receptors, ion channels, and kinases. These changes in gene expression can lead to hyperexcitability in that cell. TRPC5 protein may form homomultimeric species such as a homo-TRPC5 tetramer, or it may form heteromultimeric structures with other transient receptor proteins such as TRPC1, TRPC3, and TRPC4. The term TRPC5 is used generically to include either polymeric form. Compounds that can modulate the function of TRPC5, such as the compounds described in this patent application, can maintain calcium homeostasis, modulate intracellular calcium levels, modulate membrane polarization, and potentially treat or prevent several diseases and disorders associated with calcium and/or sodium homeostasis or dys-homeostasis.