Amyloid targeting agents and methods of using the same
AssigneesThe Regents of the University of California, Amydis, Inc.
InventorsJerry Yang, Emmanuel A. Theodorakis, Stella Sarraf
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Abstract
Provided herein is the design and synthesis of novel molecular rotor fluorophores useful for detection of amyloid or amyloid like proteins. The fluorophores are designed to exhibit enhanced fluorescence emission upon associating with amyloid or amyloid like proteins as compared to unbound compound. Also disclosed herein are methods for treating diseases associated with amyloid or amyloid like proteins.
Claims18
A method for determining whether a subject is afflicted with systemic amyloidosis associated with misfolded or aggregated transthyretin, the method comprising
- (i) administering to an eye of the subject a compound of Formula (Ic) or a pharmaceutically acceptable salt thereof, and
- (ii) detecting the presence or absence of a complex of the misfolded or aggregated transthyretin with the compound, wherein the complex, if present, generates a detectible signal indicating that the subject is positive for the systemic amyloidosis;
- wherein the compound of Formula (Ic) has the structure:
- wherein
- EDG is heterocycloalkyl of no more than 10 carbons optionally substituted with one or more R17,
- each R17 is independently halogen, —OR18, —NR19R20, C1-C10 alkyl, or C1-C10 heteroalkyl;
- each of R18, R19 and R20 is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, or cycloalkyl of no more than 10 carbon atoms, each of which except for hydrogen is optionally substituted with one or more R21;
- each R21 is independently halogen, —OR22, —NR23R24, C1-C10 alkyl, C1-C10 heteroalkyl, cycloalkyl of no more than 10 carbon atoms, heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than 10 carbon atoms, or heteroaryl of no more than 10 carbon atoms;
- each of R22, R23 and R24 is independently hydrogen or C1-C10 alkyl;
- Ar is arylene of no more than 14 carbon atoms optionally substituted with one or more R1;
- each R1 is independently halogen, —OR2, —NR3R4, C1-C10 alkyl, or C1-C10 heteroalkyl,
- each of R2, R3 and R4 is independently hydrogen, C1-C10 alkyl, or C1-C10 heteroalkyl;
- R84 is hydrogen or C1-C10 alkyl;
- EWG is halogen, —CN, -NO2, or methyl;
- WSG is:
- n is an integer from 2-50;
- R81 is hydrogen, a C1-C10 alkyl, a C2-C10 alkenyl, or a C2-C10 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more C1-C10 alkyl, C1-C10 heteroalkyl, cycloalkyl of no more than 10 carbon atoms, heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than 10 carbon atoms, or heteroaryl of no more than 10 carbon atoms;
- each R82 is independently hydrogen or C1-C10 alkyl;
- X is C—O or SO2;
- and
- Y is NH or S.
A method for determining whether a subject is afflicted with systemic amyloidosis associated with misfolded or aggregated transthyretin, the method comprising:
- (i) administering to an eye of the subject a compound or a pharmaceutically acceptable salt thereof having the structure:
- and
- (ii) detecting the presence or absence of a complex of the misfolded or aggregated transthyretin with the compound, wherein the presence of the complex generates a detectible signal indicating that the subject is positive for systemic amyloidosis.
A method for detecting a misfolded or aggregated transthyretin in a subject having systemic amyloidosis, the method comprising:
- (i) administering to an eye of the subject a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:
- and
- (ii) detecting a signal generated by a complex of the misfolded or aggregated transthyretin with the compound or the pharmaceutically acceptable salt thereof;
- thereby detecting the misfolded or aggregated transthyretin in the subject having systemic amyloidosis.
Dependencies are inferred from the claim text.