IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0830731
(2013-03-14)
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등록번호 |
US-9169214
(2015-10-27)
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발명자
/ 주소 |
- Graef, Isabella A.
- Alhamadsheh, Mamoun M.
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출원인 / 주소 |
- The Board of Trustees of the Leland Stanford Junior University
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대리인 / 주소 |
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인용정보 |
피인용 횟수 :
1 인용 특허 :
39 |
초록
▼
Disclosed herein are compounds and compositions thereof which find use in increasing stability of proteins particularly proteins that tend to misfold and form aggregates. Also provided herein are methods for using these compounds and compositions for increasing stability of proteins and thereby decr
Disclosed herein are compounds and compositions thereof which find use in increasing stability of proteins particularly proteins that tend to misfold and form aggregates. Also provided herein are methods for using these compounds and compositions for increasing stability of proteins and thereby decreasing aggregate formation by these proteins. Also disclosed herein are heterobifunctional compounds that include a TTR binding compound connected to a targeting moiety via a linker, for use in disrupting PPIs of a target protein.
대표청구항
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1. A composition comprising a compound of Compound (VI): where n is 3;R1 is a short chain alkyl having 1 to 4 carbon atoms;R2 is hydrogen;R3 is a short chain alkyl having 1 to 4 carbon atoms;Xa is C(R4)(R5), O, N—R5 or S; where R4 and R5 are independently selected from hydrogen, alkyl, substituted a
1. A composition comprising a compound of Compound (VI): where n is 3;R1 is a short chain alkyl having 1 to 4 carbon atoms;R2 is hydrogen;R3 is a short chain alkyl having 1 to 4 carbon atoms;Xa is C(R4)(R5), O, N—R5 or S; where R4 and R5 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkoxy,aryloxy, hydroxyl, heterocyclic group, halogen, nitro, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;Ra is CHO, COOH, COOCH3, COOR6, CONR7R8, tetrazolyl, CONHOH, B(OH)2, CONHSO2Ar, CONHCH(R9)COOH, hydrogen, an acyl, substituted acyl, carboxyl, alkoxycarbonyl, heterocyclic group, sulfonamide, sulfonyl fluoride, thioester, or substituted alkoxycarbonyl;Rb is CHO, COOH, COOCH3, COOR6, CONR7R8, tetrazolyl, CONHOH, B(OH)2, CONHSO2Ar, CONHCH(R9)COOH, a halogen or heterocyclic group;R6 is alkyl, haloalkyl, cycloalkyl, or heterocyclyl;R7 and R8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl; andR9 is the side chain of a naturally occurring α-amino carboxylic acid; or a pharmaceutically acceptable salt, ester, enol ether, enol ester, acetal, amide, ketal, orthoester, hemiacetal, hemiketal, hydrate, solvate or prodrug thereof. 2. The composition of claim 1, wherein the compound has the structure of Compound (VIIc): or a pharmaceutically acceptable salt, ester, enol ether, enol ester, acetal, amide, ketal, orthoester, hemiacetal, hemiketal, hydrate, solvate or prodrug thereof. 3. A composition comprising a compound of Compound (VIIa): where Ra is OH, CHO, COOH, CONH2, CONH(OH), COOR6, CONHR6; andR6 is straight of branched alkyl of 1-3 carbon atoms;or a pharmaceutically acceptable salt, ester, enol ether, enol ester, acetal, amide, ketal, orthoester, hemiacetal, hemiketal, hydrate, solvate or prodrug thereof. 4. A pharmaceutical composition comprising the composition of claim 3 and a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, a pharmaceutically acceptable excipient or a pharmaceutically acceptable adjuvant. 5. A composition comprising a compound of Compound (VIIb): where Ra is COOH, CONH2, CONH(OH), COOR6, CONHR6; andR6 is straight of branched alkyl of 1-3 carbon atoms;or a pharmaceutically acceptable salt, ester, enol ether, enol ester, acetal, amide, ketal, orthoester, hemiacetal, hemiketal, hydrate, solvate or prodrug thereof. 6. A pharmaceutical composition comprising the composition of claim 5 and a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, a pharmaceutically acceptable excipient or a pharmaceutically acceptable adjuvant. 7. A method of stabilizing TTR and/or decreasing amyloid fibril formation in a tissue or biological fluid, the method comprising contacting TTR with the pharmaceutical composition of claim 1, wherein the contacting stabilizes TTR and/or decreases TTR amyloid fibril formation. 8. The method of claim 7, wherein the composition further comprises at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, a pharmaceutically acceptable excipient and a pharmaceutically acceptable adjuvant. 9. A method of stabilizing TTR and/or decreasing amyloid fibril formation in a tissue or biological fluid, the method comprising contacting TTR with the pharmaceutical composition of claim 2, wherein the contacting stabilizes TTR and/or decreases TTR aggregation and amyloid fibril formation. 10. The method of claim 9, wherein the composition further comprises at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, a pharmaceutically acceptable excipient and a pharmaceutically acceptable adjuvant. 11. A method of inhibiting TTR misfolding, comprising contacting the TTR with a compound of claim 1. 12. A method of inhibiting dissociation of a TTR tetramer by kinetic stabilization of the native state of the TTR tetramer, comprising contacting the tetramer with a compound of claim 1. 13. A method of inhibiting protein-protein interactions, comprising contacting TTR with a compound of claim 1. 14. A method of claim 13, wherein the compound is a hetero-bifunctional molecule. 15. A method of measuring TTR tetramer levels in biological fluids or tissues, comprising contacting the TTR tetramer with a labeled compound of claim 1. 16. A method of determining the presence and/or concentration of TTR in a sample comprising biological fluid or tissue comprising the steps of adding a labeled compound of claim 1 to the sample, binding of the labeled compound to TTR and measuring the presence of the labeled compound. 17. A method of determining the presence and/or concentration of TTR in a sample comprising biological fluid or tissue, comprising: adding a labeled compound of claim 1 to the sample,allowing binding of the labeled compound to TTR, andmeasuring distance-dependent energy transfer between the labeled compound bound to a T4 binding pocket and a labeled compound and/or peptide and/or protein bound to an orthogonal binding surface on the TTR tetramer. 18. A method of determining efficacy of a candidate compound and/or method designed to stabilize TTR and/or decrease TTR dissociation and/or decrease TTR amyloid fibril formation and/or to alter TTR protein expression levels, comprising: contacting a TTR tetramer in a sample comprising biological fluid or tissue with a labeled compound of claim 1 in the presence of the candidate compound and/or the method, andmeasuring the presence of the labeled compound. 19. A method of determining efficacy of a candidate compound and/or method designed to stabilize TTR and/or decrease TTR dissociation and/or decrease TTR amyloid fibril formation and/or to alter TTR protein expression levels in a sample comprising biological fluid or tissue, comprising: adding of a labeled compound of claim 1 to the sample,allowing binding of the labeled compound to TTR, andmeasuring the distance-dependent energy transfer between the labeled compound bound to a T4 binding pocket and a labeled compound and/or peptide and/or protein bound to an orthogonal binding surface on the TTR tetramer. 20. The composition of claim 1, wherein n is 3. 21. The composition of claim 20, wherein Xa is O. 22. The composition of claim 1, wherein R1 is methyl. 23. The composition of claim 1, wherein R3 is methyl. 24. The composition of claim 23, wherein Xa is O. 25. The composition of claim 1, wherein Ra is carboxyl. 26. The composition of claim 1, wherein Rb is selected from bromo, chloro and fluoro. 27. The composition of claim 1, wherein Rb is fluoro. 28. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, a pharmaceutically acceptable excipient or a pharmaceutically acceptable adjuvant.
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