Compounds and compositions that bind and stabilize transthyretin and their use for inhibiting transthyretin amyloidosis and protein-protein interactions
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/415
C07D-231/12
C07D-237/08
출원번호
US-0480139
(2017-04-05)
등록번호
US-9913826
(2018-03-13)
발명자
/ 주소
Graef, Isabella A.
Alhamadsheh, Mamoun M.
출원인 / 주소
The Board of Trustees of the Leland Stanford Junior University
대리인 / 주소
Baba, Edward J.
인용정보
피인용 횟수 :
0인용 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▼
1. A method of treating a transthyretin amyloid disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of Compound VIIa: where Ra is selected from the group consisting of OH, CHO, COOH, CONH2, CONH(OH), COOR6, and CONHR6; andR6 is straight or br
1. A method of treating a transthyretin amyloid disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of Compound VIIa: where Ra is selected from the group consisting of OH, CHO, COOH, CONH2, CONH(OH), COOR6, and CONHR6; andR6 is straight or branched alkyl of 1-3 carbon atoms;or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein Ra is selected from the group consisting of COOH CONH2, CONH(OH), COOR6, and CONHR6. 3. The method of claim 1, wherein Compound VIIa has a structure of Compound VIIc or a pharmaceutically acceptable salt thereof. 4. The method of claim 1, wherein said transthyretin amyloid disease is selected from the group consisting of familial amyloid polyneuropathy, familial amyloid cardiomyopathy, senile systemic amyloidosis, central amyloidosis, ocular amyloidosis, Leptomeningeal amyloidsis, oculoleptomengial amyloidosis, vitreous amyloidosis, gastrointestinal amyloidosis, neuropathic amyloidosis, non-neuropathic amyloidosis, non-hereditary amyloidosis, reactive/secondary amyloidosis, cerebral amyloidosis. 5. The method of claim 1, wherein said transthyretin amyloid disease is familial amyloid polyneuropathy. 6. The method of claim 1, wherein said transthyretin amyloid disease is familial amyloid cardiomyopathy. 7. The method of claim 1, wherein said transthyretin amyloid disease is senile systemic amyloidosis. 8. The method of claim 1, wherein said transthyretin amyloid disease is ocular amyloidosis. 9. The method of claim 1, wherein said transthyretin amyloid disease is Leptomeningeal amyloidosis. 10. The method of claim 1, wherein said transthyretin amyloid disease is selected from the group consisting of Alzheimer's disease, Creutzfeldt Jakob disease, Gerstmann-Sträussler-Scheinker (GSS), fatal familial insomnia, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Down Syndrome, multiple sclerosis, polyneuropathy, Guillain-Barre' syndrome, macular degeneration, glaucoma, type II diabetes, and medullary carcinoma of the thyroid. 11. The method of claim 1, wherein said transthyretin amyloid disease is amyotrophic lateral sclerosis (ALS). 12. The method of claim 3, wherein said transthyretin amyloid disease is selected from the group consisting of familial amyloid polyneuropathy, familial amyloid cardiomyopathy, senile systemic amyloidosis, central amyloidosis, ocular amyloidosis, Leptomeningeal amyloidosis, oculoleptomengial amyloidosis, vitreous amyloidosis, gastrointestinal amyloidosis, neuropathic amyloidosis, non-neuropathic amyloidosis, non-hereditary amyloidosis, reactive/secondary amyloidosis, cerebral amyloidosis. 13. The method of claim 3, wherein said transthyretin amyloid disease is familial amyloid polyneuropathy. 14. The method of claim 3, wherein said transthyretin amyloid disease is familial amyloid cardiomyopathy. 15. The method of claim 3, wherein said transthyretin amyloid disease is senile systemic amyloidosis. 16. The method of claim 3, wherein said transthyretin amyloid disease is ocular amyloidosis. 17. The method of claim 3, wherein said transthyretin amyloid disease is Leptomeningeal amyloidosis. 18. The method of claim 3, wherein said transthyretin amyloid disease is selected from the group consisting of Alzheimer's disease, Creutzfeldt Jakob disease, Gerstmann-Sträussler-Scheinker (GSS), fatal familial insomnia, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Down Syndrome, multiple sclerosis, polyneuropathy, Guillain-Barre' syndrome, macular degeneration, glaucoma, type II diabetes, and medullary carcinoma of the thyroid. 19. The method of claim 3, wherein said transthyretin amyloid disease is Alzheimer's disease. 20. The method of claim 3, wherein said transthyretin amyloid disease is amyotrophic lateral sclerosis (ALS).
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