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THERAPEUTIC AGENT FOR COGNITION DISORDER INDUCED BY AMYLOID β-PROTEIN

Foreign code F160008820
File No. (S2015-0044-N0)
Posted date Aug 10, 2016
Country WIPO
International application number 2015JP079120
International publication number WO 2016060190
Date of international filing Oct 15, 2015
Date of international publication Apr 21, 2016
Priority data
  • P2014-211671 (Oct 16, 2014) JP
Title THERAPEUTIC AGENT FOR COGNITION DISORDER INDUCED BY AMYLOID β-PROTEIN
Abstract The present invention addresses the problem of providing a therapeutic agent for cognition disorders induced by amyloid β-protein, the therapeutic agent functioning by a mechanism in which amyloid β-protein is involved but which is different from conventional mechanisms. This medicinal composition, which is for the treatment of cognition disorders induced by amyloid β-protein, comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of either the peptide according to the invention or a pharmaceutically acceptable ester, amide, prodrug, or salt thereof.
Outline of related art and contending technology BACKGROUND ART
Alzheimer's disease, cognitive decline (or remembering) the main condition that neurological disease. In particular in elderly is even though the predilection, there is no effective therapeutic, are worn out in aging society and the serious problem in developed countries. In the postmortem brain of Alzheimer's disease patients which neuritic plaques observed, this is' amyloid β protein ' aggregates with are known. Then, the amyloid β protein is the main cause of Alzheimer's disease is, by numerous studies in the widely accepted.
Amyloid β protein, a precursor thereof 'the amyloid precursor protein' generated from. The amyloid precursor protein and, present on the nerve cells in the membrane protein. In the normal brain, its extracellular domain α secretase, γ-secretase in the cell membrane and then are cut in the domain, the peptide is referred to as p3 outside of the cell production, is released. This is' non-amyloid generation path ' known as, amyloid β protein is not generated (non-patent document 1). In the normal brain, but the extracellular domain of the β-secretase is several % to truncated, secreted extracellular amyloid β protein are. However, in the brain Alzheimer's disease, amyloid β production amount of the protein will be increased, amyloid β protein aggregation high so as to produce a species are considered to be. Amyloid β protein with this property, finally Alzheimer's disease patients of senile plaques formed (amyloid aggregates), deposition is observed in the brain.
Amyloid β protein is found to have a cut, gradually aggregated, finally senile plaques (amyloid aggregates) are formed, agglomeration processes' oligomeric forms (amyloid β protein that associated with the several) ' in, known to be strong neurotoxicity. The amyloid β protein oligomeric forms is, memory, learning of the neural phenomenon essential to inhibit synaptic plasticity, in vitro, both in vivo have been reported (non-patent document 2, 3). In addition, this oligomer administered to the body in the mouse brain, storage, can be lost to the learning ability have been reported (non-patent document 4, 5). A recent study, and long-term exposure to this oligomeric forms, such as neuronal cell death was also has been reported (non-patent document 6), to cause the onset of Alzheimer's disease has been paid attention as a substance.
In this way, as the cause of the amyloid β protein Alzheimer's disease is widely recognized that regardless of the fact that, currently clinically used in the therapeutic agent is Alzheimer's disease, amyloid β protein in such a manner that this design is not. Specifically, used as a therapeutic agent Alzheimer's disease (Patent Document 1) memantine or donepezil (Patent Document 2) is, and the acetylcholinesterase inhibitor respectively act as NMDA receptor inhibitors, amyloid β protein does not interact with. Since the agent is a so-called address, a dramatic improvement in the effect for Alzheimer's disease is at present.
In response to such a background, based on the mechanism of action (amyloid protein) new Alzheimer's development of therapeutics has been promoted. 1 Is one, the amyloid precursor protein from the production of amyloid β protein and attempted to attempt, the development of secretase control agent (non-patent document 1). Among them, development of γ secretase inhibitors and the most advanced, Begacestat Semagacestat (Patent Document 3) or the like (Patent Document 4), and clinical development efforts have been performed. Another has attracted attention as a therapy is, amyloid β protein in the brain is removed and antibody-recognized, antibody therapy. Actually, solanezumab Bapineuzumab (Patent Document 5) or the like, clinical development has progressed so far is MIMIC.
However, with the center of the present development of amyloid protein Alzheimer's mechanism of action and there are problems that the therapeutic agent may be known. With respect to the γ secretase inhibitors, γ secretase substrates in the first place as well as the amyloid precursor protein, are known to be near about 100 (non-patent document 7). And includes an, important cell differentiation which may include Notch receptor (non-patent document 8), concern about side effects. Actually, as was a strong candidate for the γ secretase inhibitors Semagacestat is, developed in the year 2010 the third phase clinical trials are terminated. Anti-amyloid β antibody for the antibody therapy, vasculitis and vascular cerebral edema and the like which can occur, in fact, is promising as a therapeutic agent was also Bapineuzumab antibody, was developed in 2012 is stopped.
In addition, the stroma of the γ secretase, cut the extracellular domain of the amyloid peptide may be ejected in some known (non-patent document 9, 10). These peptides are indicative of the activity since the γ secretase, fragment was cut to a biomarker of the invention of the Alzheimer's disease are some (Patent Document 6, 7). Also, referred to as Alcadein-β is membrane protein in vivo, cleaved by γ-secretase, by may be cut by further α secretase, 37 amino acid peptide (VLSSQQFLHRGHQPPPEMAGHSLASSHRNSMIPSAAT) also known being produced in the (non-patent document 11).
Scope of claims (In Japanese)[請求項1]
以下の(a)~(e)よりなる群より選ばれるいずれかに記載のペプチド:
(a)配列番号1に示すアミノ酸配列を含むペプチド;
(b)配列番号1に示すアミノ酸配列からなるペプチド;
(c)配列番号1のアミノ酸配列において、1~3個のアミノ酸が欠失、置換、挿入、及び/又は付加されたアミノ酸配列からなり、かつアミロイドβ蛋白質により誘発される認知障害に対する治療効果を有するペプチド;及び
(d)配列番号1のアミノ酸配列に対して、90%以上の同一性を有するアミノ酸配列を有し、かつアミロイドβ蛋白質により誘発される認知障害に対する治療効果を有するペプチド。
[請求項2]
配列番号2に示すアミノ酸配列からなる、請求項1に記載のペプチド。
[請求項3]
配列番号3に示すアミノ酸配列からなる、請求項1に記載のペプチド。
[請求項4]
合成ペプチドである、請求項1に記載のペプチド。
[請求項5]
治療上有効量の請求項1に記載のペプチド又はその医薬的に許容可能なエステル、アミド、プロドラッグ若しくは塩及び医薬的に許容可能な担体を含む、アミロイドβ蛋白質により誘発される認知障害の治療のための医薬組成物。
[請求項6]
腹腔内投与されるものである、請求項5に記載の組成物。
[請求項7]
局所投与されるものである、請求項5に記載の組成物。
[請求項8]
別のアルツハイマー病治療剤と併用される、請求項5に記載の組成物。
[請求項9]
アミロイドβ蛋白質により誘発される認知障害の治療に使用するための請求項1に記載のペプチド又はその医薬的に許容可能なエステル、アミド、プロドラッグ若しくは塩。
[請求項10]
治療上有効量の請求項1に記載のペプチド又はその医薬的に許容可能なエステル、アミド、プロドラッグ若しくは塩を治療を必要とする患者に投与することを含む、アミロイドβ蛋白質により誘発される認知障害の治療方法。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NATIONAL UNIVERSITY CORPORATION HOKKAIDO UNIVERSITY
  • NATIONAL UNIVERSITY CORPORATION OKAYAMA UNIVERSITY
  • Inventor
  • SUZUKI Toshiharu
  • BAN Saori
  • INOUE Tsuyoshi
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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