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EP-4741012-A2 - COMPOSITIONS AND METHODS FOR REDUCING AMYLOID BETA FORMATION AND COMPOSITION THEREFORE

EP4741012A2EP 4741012 A2EP4741012 A2EP 4741012A2EP-4741012-A2

Abstract

The present invention provides a pharmaceutical composition for use in treating Alzheimer's Disease (AD), the composition comprising mirodenafil or a pharmaceutically acceptable salt, solvate, and hydrate thereof, wherein the composition suppresses DKK-1 to activate Wnt Signaling to restore Synaptic Plasticity and suppresses Positive Feedback Loop of Aβ production to reduce formation of APP (Amyloid precursor Protein) and Aβ accumulation.

Inventors

  • CHOUNG, JAI JUN
  • CHOI, YOON PYO
  • KANG, Byungwoo
  • KIM, Fred
  • CHOUNG, Mi Sun

Assignees

  • Aribio Co., Ltd.
  • SK Chemicals Co., Ltd.

Dates

Publication Date
20260513
Application Date
20200324

Claims (7)

  1. A pharmaceutical composition for use in treating Alzheimer's Disease (AD), the composition comprising mirodenafil or a pharmaceutically acceptable salt, solvate, and hydrate thereof, wherein the composition suppresses DKK-1 to activate Wnt Signaling to restore Synaptic Plasticity and suppresses Positive Feedback Loop of Aβ production to reduce formation of APP (Amyloid Precursor Protein) and Aβ accumulation.
  2. The composition for use according to claim 1, wherein the composition induces an improvement in cognitive capacity and behavioral learning skills, as determined using a passive avoidance test or a Morris Water Maze test.
  3. The composition for use according to claim 1, wherein the composition inhibits formation of Aβ aggregation by reducing formation of Aβ Oligomer or Fibril.
  4. The composition for use according to claim 1, wherein the composition inhibits β-Amyloidogenic Processing through BACE-1 reduction.
  5. The composition for use according to claim 1, wherein the composition reduces extracellular formation and accumulation of amyloid beta monomer, oligomer, and/or amyloid beta fibril and plaque by vasodilation.
  6. The composition for use according to claim 1, wherein the composition reduces neuronal cell death and enhances neurogenesis, synaptogenesis, or angiogenesis by activating NO (Nitric Oxide)/cGMP (Cyclic Guanosine Monophosphate)/PKG (Protein Kinase G), CREB (Cyclic AMP (Adenosine Monophosphate) Response Element Binding Protein) Pathway.
  7. The composition for use according to claim 1, wherein the composition activates Autophagy to remove intracellular Toxic Soluble Aβ Oligomer to suppress formation and accumulation of Aβ Fibril/Plaque.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of priority from U.S. Provisional Application Serial No. 62/822,975, filed March 24, 2019, the contents of which are incorporated herein by reference. FIELD OF THE INVENTION The present invention is related to methods for reducing amyloid beta formation and for treating diseases associated with the accumulation of amyloid beta. BACKGROUND OF THE INVENTION Dementia refers to a clinical disease that suffers from multiple cognitive impairment (or MCD, Multiple Cognitive Deficits) as an acquired brain disease that shows multifaceted pathogenesis caused by a variety of genetic and environmental risk factors. A representative of diseases causing dementia is Alzheimer's disease, mainly endemic in senior people and contributed to 60-70% of the all dementia (Ann Neurol. 1993 May; 33(5): 494-501.). Recent rapid aging of population, more progressive dementia in older people by Alzheimer's has increased and so does the need for treatment of dementia. However, the difficulties of research and development in additional low rate of success down the process of development of new therapeutics and treatment method for dementia. Based on 2014 GBI Research data, the success rate for final approval of a therapeutics for Alzheimer's disease is less than 1%, as 72% in clinical phase II, 92% of clinical phase III, and 99.6% of NDA application failed and about 80% of the currently on-going pipelines are only for "exploratory and/or pre-clinical stage." The current conventional list of FDA approved drugs include AChE (Acetylcholinesterase) Inhibitor and NMDA (N-Methyl-D- Aspartate) Receptor Antagonist, used also in combination with antioxidant, NSAID (non-steroidal anti-inflammatory drugs), anti-inflammatory agents, statin formulations, or Hormone formulations, etc. However, these drugs are used only to relieve symptoms and delay or improvement of cognitive disorders, but there is no fundamental treatment for dementia at this moment. Representative AChE Inhibitors includes Donepezil (Aricept™ ), Galantamine (Reminyl™ ), Rivastigmine (ENA-713, Exelon™ ), etc., and these drugs temporarily increase the concentration of neurotransmitters Acetylcholine to provide symptomatic treatment. In addition, these drugs are prescribed for patients with mild to moderate Alzheimer's disease, vascular dementia, dementia by Parkinson's disease, and stroke or cerebral subcortical ischemic vascular disease (J Korean Med Assoc 2009; 52(4): 417-425.). Typical NMDA Receptor Antagonist includes Memantine (Ebixa™), which causes excitotoxicity to inhibit glutamate transportation system which blocks synaptic plasticity to effectively reduce neuronal degeneration. Memantine was confirmed to be effective in the moderate or more dementia and Lewy body dementia with relatively low side effect, but showed only limited activity in more earlier state of disease (Arch Neurol 2011 Aug; 68 (8): 991-8). Thus, it was used more with ChE inhibitors and in mild and severe dementia than monotherapy. However, so far no clear evidence was found that the combination of AChE inhibitors and Menantine is more effective than AChE alone and additional study is required (Brain Neurorehabil 2015 Mar; 8(1): 19-23.). However, even though these drugs have been used for treatment of dementia and Alzheirmer's disease for a long time, there is no clear standard for the usage and furthermore, even at the maximum recommended human dose (MRHD), either there was only no improvement or continued progress of the disease to lead the patients to the terminal stage in the treated patients, there has been a continuous concern with the usage of these drugs. However, until now in the absence of any therapeutics with confirmed efficacy, there is no alternatives but to continue the effort to develop new treatment for dementia (Korean J Biol Psychiatry 2016 May; 23(2): 48-56.). The main targets of candidates for dementia treatments that have been developed so far include: (1) inhibitors of BACE-1 (β-Secretase 1) or γ-Secretase Inhibitor to inhibit production of Aβ (Amyloid β), (2) Anti-Aβ Monoclonal Antibody to remove Aβ (Amyloid β), (3) Tau Aggregation Inhibitor and (One Amino Acid Kinase) TAOK Inhibitor to inhibit Tau Aggregation and Phosphorylation, (4) AchE Inhibitor and NMDA Receptor Antagonist to block AChE and NMDA Receptor, etc. Recently, pipelines targeting Aβ Plaque and Tau proteins have increased, among which about 70-80% of the candidates target suppression of Aβ production or removal Aβ. In addition, about 30% of the pipelines is biopharmaceuticals with dominantly high ratio of monoclonal antibody or peptide. However, due to the recent failures of clinical trials of candidates with high expectation, including Anti-Aβ Monoclonal Antibody targeting Aβ for targeted such as Aducanumab (Biogen), Solanezumab (Eli Lilly), and Gantenerumab (Roche), the assumption of Aβ as the target for treatment of dementia became uncertain. N