公开(公告)号：KR100883132B1

公开(公告)日：2009-02-10

申请号：KR1020070107136

申请日：2007-10-24

Applicant: 재단법인서울대학교산학협력재단

Inventor： 서정헌

IPC: A61K33/24 ,  A61K31/53

CPC classification number: C07D413/14 ,  A61K31/53 ,  C07D417/14

Abstract: 본 발명은 아밀로이드 형성 펩타이드 또는 단백질의 가용성 회합체를 선택적으로 인식하여 절단하는 합성 절단제 및 이 합성 절단제를 사용하여 아밀로이드 형성 펩타이드 또는 단백질의 가용성 회합체를 선택적으로 절단하는 방법에 관한 것이다.
아밀로이드, 펩타이드, 단백질, 회합체, 절단제

公开(公告)号：KR1020080036916A

公开(公告)日：2008-04-29

申请号：KR1020070075809

申请日：2007-07-27

Applicant: 재단법인서울대학교산학협력재단

Inventor： 서정헌

IPC: C07K1/00 ,  A61K47/48 ,  C07F15/06

CPC classification number: C07D307/78 ,  A61K47/545 ,  A61K47/547 ,  C07D209/04 ,  C07D235/04 ,  C07D251/12 ,  C07D255/02 ,  C07D257/00 ,  C07D257/04 ,  C07D257/10 ,  C07D263/54 ,  C07D273/00 ,  C07D277/62 ,  C07D285/00 ,  C07D333/52 ,  C07D471/12 ,  C07D471/22 ,  C07D498/12 ,  C07K1/00 ,  A61K47/50 ,  C07F15/06

Abstract: A cleavage agent is provided to inhibit the biological activity of a soluble assembly of an amyloidogenic peptide or a protein by effectively cleaving the assembly of the amyloidogenic peptide or the protein, thereby being used in order to prevent or treat amyloidosis. A cleavage agent selectively acting on soluble assembly of an amyloidogenic peptide or a protein is represented by the formula(1) of (R)n-(L)m-Z. In the formula(1), R is a target recognition site independently selected from the group consisting of A, A-(Y)o-(CH2)p-(Y)o-A, A-(CH=CH)-A, A-(Y)o-(CH2)p-(Y)o-A-(Y)o-(CH2)p-(Y)o-A and A-(Y)o-(CH2)p-(Y)o-A-(Y)o-(CH2)p-(Y)o-A-(Y)o-(CH2)p-(Y)o-A, where A is independently C6-14 aryl, or 5- to 14-membered heteroaryl having at least one hetero atom selected from the group consisting of O, S and N, wherein aryl or heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of C1-15 alkyl, hydroxy, C1-15 alkoxy, C1-15 alkylcarbonyloxy, C1-15 alkylsulfonyloxy, amino, mono or di(C1-15)alkylamino, C1-15 alkylcarbonylamino, C1-15 alkylsulfonylamino, C3-15 cycloalkylamino, formyl, C1-15 alkylcarbonyl, carboxy, C1-15 alkyloxycarbonyl, carbamoyl, mono or di(C1-15)alkylcarbamoyl, C1-15 alkylsulfanylcarbonyl, C1-15 alkylsulfanylthiocarbonyl, C1-15 alkoxycarbonyloxy, carbamoyloxy, mono or di(C1-15)alkylcarbamoyloxy, C1-15 alkylsulfanylcarbonyloxy, C1-15 alkoxycarbonylamino, ureido, mono or di or tri(C1-15)alkylureido, C1-15 alkylsulfanylcarbonylamino, mercapto, C1-15 alkylsulfanyl, C1-15 alkyldisulfanyl, sulfo, C1-15 alkoxysulfonyl, sulfamoyl, mono or di(C1-15) alkylsulfamoyl, tri(C1-15) alkylsilanyl and halogen; Y is O or N-Z, wherein Z is hydrogen or C1-9 alkyl; L is a linker; Z is a metal ion-ligand complex as a catalytic site; n is an integer from 1 to 6; m and o are independently 0 or 1; p is an integer from 0 to 5. The cleavage agent is characterized in that it cleaves an oligomer of Abeta40 or Abeta40, an oligomer of amylin, or an oligomer of alpha-synuclein.

Abstract translation: 提供裂解剂以通过有效地切割淀粉样蛋白原肽或蛋白质的组合来抑制淀粉样蛋白原肽或蛋白质的可溶性组装体的生物学活性，由此用于预防或治疗淀粉样变性。 选择性地作用于淀粉状蛋白原肽或蛋白质的可溶性组装的切割剂由（R）n-（L）m-Z的式（1）表示。 在式（1）中，R是独立地选自A，A-（Y）o-（CH 2）p - （Y）o A，A-（CH = CH）-A，A - （Y）o-（CH 2）p - （Y）oA-（Y）o-（CH 2）p - （Y）o A和A-（Y）o-（CH 2） ） - （CH 2）p - （Y）oA-（Y）o-（CH 2）p - （Y）o A，其中A独立地为C 6-14芳基或具有至少一个杂原子的5至14元杂芳基 选自O，S和N的原子，其中芳基或杂芳基是未取代的或被至少一个独立地选自C 1-15烷基，羟基，C 1-15烷氧基，C 1-15烷基羰基氧基， C1-15烷基磺酰氧基，氨基，单或二（C1-15）烷基氨基，C1-15烷基羰基氨基，C1-15烷基磺酰基氨基，C3-15环烷基氨基，甲酰基，C1-15烷基羰基，羧基，C1-15烷氧基羰基，氨基甲酰基，单或 二（C1-15）烷基氨基甲酰基，C1-15烷基硫烷基羰基，C1-15烷基硫烷基硫代羰基，C1-15烷氧基羰基氧基，氨基甲酰氧基，单或二（C1-15）烷基氨基甲酰氧基，C1-15烷基硫烷基羰基 羟基，C1-15烷氧基羰基氨基，脲基，一或二或三（C1-15）烷基脲基，C1-15烷基硫基羰基氨基，巯基，C1-15烷基硫烷基，C1-15烷基二硫烷基，磺基，C1-15烷氧基磺酰基，氨磺酰基，单或二 （C1-15）烷基氨磺酰基，三（C1-15）烷基硅烷基和卤素; Y是O或N-Z，其中Z是氢或C1-9烷基; L是连接体; Z是金属离子 - 配体络合物作为催化位点; n是1至6的整数; m和o独立地为0或1; p是0至5的整数。切割剂的特征在于其切割Aβ40或Abeta40的寡聚物，胰岛淀粉样多肽的寡聚物或α-突触核蛋白的寡聚物。

公开(公告)号：KR1020080036936A

公开(公告)日：2008-04-29

申请号：KR1020070107136

申请日：2007-10-24

Applicant: 재단법인서울대학교산학협력재단

Inventor： 서정헌

IPC: A61K33/24 ,  A61K31/53

CPC classification number: C07D413/14 ,  A61K31/53 ,  C07D417/14

Abstract: A cleavage agent is provided to recognize an assembly of an amyloidogenic peptide or a protein and cleave a peptide bond rapidly, thereby inhibiting the biological activity of a soluble oligomer of the amyloidogenic peptide or the protein when various kinds of bio-molecules exist. A cleavage agent selectively acting on soluble assembly of an amyloidogenic peptide or a protein is represented by the formula(1) of (R)n-(L)m-Z. In the formula(1), R is a target recognition site independently selected from the group consisting of A, A-(Y)o-(CH2)p-(Y)o-A, A-(CH=CH)-A, A-(Y)o-(CH2)p-(Y)o-A-(Y)o-(CH2)p-(Y)o-A and A-(Y)o-(CH2)p-(Y)o-A-(Y)o-(CH2)p-(Y)o-A-(Y)o-(CH2)p-(Y)o-A, where A is independently C6-14 aryl, or 5- to 14-membered heteroaryl having at least one hetero atom selected from the group consisting of O, S and N, wherein aryl or heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of C1-15 alkyl, hydroxy, C1-15 alkoxy, C1-15 alkylcarbonyloxy, C1-15 alkylsulfonyloxy, amino, mono or di(C1-15)alkylamino, C1-15 alkylcarbonylamino, C1-15 alkylsulfonylamino, C3-15 cycloalkylamino, formyl, C1-15 alkylcarbonyl, carboxy, C1-15 alkyloxycarbonyl, carbamoyl, mono or di(C1-15)alkylcarbamoyl, C1-15 alkylsulfanylcarbonyl, C1-15 alkylsulfanylthiocarbonyl, C1-15 alkoxycarbonyloxy, carbamoyloxy, mono or di(C1-15)alkylcarbamoyloxy, C1-15 alkylsulfanylcarbonyloxy, C1-15 alkoxycarbonylamino, ureido, mono or di or tri(C1-15)alkylureido, C1-15 alkylsulfanylcarbonylamino, mercapto, C1-15 alkylsulfanyl, C1-15 alkyldisulfanyl, sulfo, C1-15 alkoxysulfonyl, sulfamoyl, mono or di(C1-15) alkylsulfamoyl, tri(C1-15) alkylsilanyl and halogen; Y is O or N-Z, wherein Z is hydrogen or C1-9 alkyl; L is a linker; Z is a metal ion-ligand complex as a catalytic site where the metal ion is selected from the group consisting of Co^3+, Cu^1+, Cu^2+, Ce^4+, Ce^5+, Cr^3+, Fe^2+, Fe^3+, Mo^4+, Ni^2+, Pd^2+, Pt^2+, V^5+ and Zr^4+; n is an integer from 1 to 6; m and o are independently 0 or 1; p is an integer from 0 to 5. A pharmaceutical composition for preventing or treating amyloidosis comprises the cleavage agent of the formula(1) and a pharmaceutically acceptable salt thereof.

Abstract translation: 提供裂解剂以识别淀粉样变性肽或蛋白质的组合并且快速切割肽键，从而当存在各种生物分子时抑制淀粉样蛋白原肽或蛋白质的可溶性低聚物的生物活性。 选择性地作用于淀粉状蛋白原肽或蛋白质的可溶性组装的切割剂由（R）n-（L）m-Z的式（1）表示。 在式（1）中，R是独立地选自A，A-（Y）o-（CH 2）p - （Y）o A，A-（CH = CH）-A，A - （Y）o-（CH 2）p - （Y）oA-（Y）o-（CH 2）p - （Y）o A和A-（Y）o-（CH 2） ） - （CH 2）p - （Y）oA-（Y）o-（CH 2）p - （Y）o A，其中A独立地为C 6-14芳基或具有至少一个杂原子的5至14元杂芳基 选自O，S和N的原子，其中芳基或杂芳基是未取代的或被至少一个独立地选自C 1-15烷基，羟基，C 1-15烷氧基，C 1-15烷基羰基氧基， C1-15烷基磺酰氧基，氨基，单或二（C1-15）烷基氨基，C1-15烷基羰基氨基，C1-15烷基磺酰基氨基，C3-15环烷基氨基，甲酰基，C1-15烷基羰基，羧基，C1-15烷氧基羰基，氨基甲酰基，单或 二（C1-15）烷基氨基甲酰基，C1-15烷基硫烷基羰基，C1-15烷基硫烷基硫代羰基，C1-15烷氧基羰基氧基，氨基甲酰氧基，单或二（C1-15）烷基氨基甲酰氧基，C1-15烷基硫烷基羰基 羟基，C1-15烷氧基羰基氨基，脲基，一或二或三（C1-15）烷基脲基，C1-15烷基硫基羰基氨基，巯基，C1-15烷基硫烷基，C1-15烷基二硫烷基，磺基，C1-15烷氧基磺酰基，氨磺酰基，单或二 （C1-15）烷基氨磺酰基，三（C1-15）烷基硅烷基和卤素; Y是O或N-Z，其中Z是氢或C1-9烷基; L是连接体; Z是金属离子 - 配体络合物作为催化位点，其中金属离子选自Co 3+，Cu 2+，Cu 2+，Ce 4+，Ce 5+，Cr 2+， 3+，Fe ^ 2 +，Fe ^ 3 +，Mo ^ 4 +，Ni ^ 2 +，Pd ^ 2 +，Pt ^ 2 +，V ^ 5 +和Zr ^ 4 +; n是1至6的整数; m和o独立地为0或1; p为0至5的整数。用于预防或治疗淀粉样变性的药物组合物包含式（1）的切割剂及其药学上可接受的盐。

公开(公告)号：KR1020080036902A

公开(公告)日：2008-04-29

申请号：KR1020060127919

申请日：2006-12-14

Applicant: 재단법인서울대학교산학협력재단

Inventor： 서정헌

IPC: C07K1/00 ,  A61K47/48 ,  B01J31/16

CPC classification number: C07D307/78 ,  A61K47/545 ,  A61K47/547 ,  C07D209/04 ,  C07D235/04 ,  C07D251/12 ,  C07D255/02 ,  C07D257/00 ,  C07D257/04 ,  C07D257/10 ,  C07D263/54 ,  C07D273/00 ,  C07D277/62 ,  C07D285/00 ,  C07D333/52 ,  C07D471/12 ,  C07D471/22 ,  C07D498/12 ,  C07K1/00 ,  A61K47/50 ,  B01J31/16

Abstract: A cleavage agent is provided to reduce the amount of soluble oligomers of an amyloidogenic peptide or a protein by connecting sites selectively recognizing Soluble assembly of the amyloidogenic peptide or a protein with reactive portions cleaving peptide bonds. A cleavage agent selectively acting on soluble assembly of an amyloidogenic peptide or a protein is represented by the formula(1) of (R)n-(L)m-Z, wherein R is a target recognition site independently selected from the group consisting of A, A-(Y)o-(CH2)p-(Y)o-A, A-(CH=CH)-A, A-(Y)o-(CH2)p-(Y)o-A-(Y)o-(CH2)p-(Y)o-A and A-(Y)o-(CH2)p-(Y)o-A-(Y)o-(CH2)p-(Y)o-A-(Y)o-(CH2)p-(Y)o-A(where A is independently C6-14 aryl, or 5- to 14-membered heteroaryl having at least one hetero atom selected from the group consisting of O, S and N, wherein aryl or heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of C1-15 alkyl, hydroxy, C1-15 alkoxy, C1-15 alkylcarbonyloxy, C1-15 alkylsulfonyloxy, amino, mono or di(C1-15)alkylamino, C1-15 alkylcarbonylamino, C1-15 alkylsulfonylamino, C3-15 cycloalkylamino, formyl, C1-15 alkylcarbonyl, carboxy, C1-15 alkyloxycarbonyl, carbamoyl, mono or di(C1-15)alkylcarbamoyl, C1-15 alkylsulfanylcarbonyl, C1-15 alkylsulfanylthiocarbonyl, C1-15 alkoxycarbonyloxy, carbamoyloxy, mono or di(C1-15)alkylcarbamoyloxy, C1-15 alkylsulfanylcarbonyloxy, C1-15 alkoxycarbonylamino, ureido, mono or di or tri(C1-15)alkylureido, C1-15 alkylsulfanylcarbonylamino, mercapto, C1-15 alkylsulfanyl, C1-15 alkyldisulfanyl, sulfo, C1-15 alkoxysulfonyl, sulfamoyl, mono or di(C1-15)alkylsulfamoyl, tri(C1-15)alkylsilanyl and halogen; Y is O or N-Z, wherein Z is hydrogen or C1-9 alkyl; L is a linker; Z is a metal ion-ligand complex as a catalytic site; n is an independent integer from 1 to 6; m and o are independently 0 or 1; p is an integer from 0 to 5). A pharmaceutical composition for preventing or treating amyloidosis such as Alzheimer's disease, type 2 diabetes mellitus, Parkinson's disease, spongiform encepahlopathies or Huntington's disease comprises the cleavage agent of the formula(1) and a pharmaceutically acceptable salt thereof.

Abstract translation: 提供裂解剂以通过连接位点选择性地识别淀粉状蛋白原肽或蛋白质的可溶性组装以切割肽键的活性部分来减少淀粉样蛋白原肽或蛋白质的可溶性寡聚体的量。 选择性地作用于淀粉状蛋白原肽或蛋白质的可溶性组装的切割剂由（R）n-（L）mZ的式（1）表示，其中R是独立地选自A， A-（Y）o-（CH 2）p - （Y）oA，A-（CH = CH）-A，A-（Y）O-（CH 2） （Y）o-（CH 2）p - （Y）o-（CH 2）p - （CH 2）p - （Y） - （Y）oA（其中A独立地为C 6-14芳基或具有至少一个选自O，S和N的杂原子的5至14元杂芳基，其中芳基或杂芳基是未取代的或被 至少一个独立地选自C1-15烷基，羟基，C1-15烷氧基，C1-15烷基羰基氧基，C1-15烷基磺酰氧基，氨基，单或二（C1-15）烷基氨基，C1-15烷基羰基氨基， C1-15烷基磺酰基氨基，C3-15环烷基氨基，甲酰基，C1-15烷基羰基，羧基，C1-15烷氧基羰基，氨基甲酰基，单或二（C1-15）烷基氨基甲酰基，C1-15烷基硫烷基羰基， C 1-15烷氧羰基氧基，氨基甲酰氧基，一或二（C1-15）烷基氨基甲酰氧基，C1-15烷基硫烷基羰基氧基，C1-15烷氧基羰基氨基，脲基，一或二或三（C1-15）烷基脲基，C1-15烷基硫基羰基氨基 ，巯基，C 1-15烷基硫烷基，C 1-15烷基二硫烷基，磺基，C 1-15烷氧基磺酰基，氨磺酰基，单或二（C1-15）烷基氨磺酰基，三（C1-15）烷基硅烷基和卤素; Y是O或N-Z，其中Z是氢或C1-9烷基; L是连接体; Z是金属离子 - 配体络合物作为催化位点; n是1至6的独立整数; m和o独立地为0或1; p是从0到5的整数）。 用于预防或治疗淀粉样变性的药物组合物，例如阿尔茨海默氏病，2型糖尿病，帕金森病，海绵状脑病或亨廷顿氏病包括式（1）的切割剂及其药学上可接受的盐。