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US 10,934,264 B2Granted
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.
Claims20
A compound of Formula (Ic), a pharmaceutically acceptable salt thereof, or a solvate thereof:
- wherein:
- EDG is heterocycloalkyl of no more than 10 carbon atoms 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 naphthyl 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 —CN;
- WSG is
- n is an integer from 2 to 10;
- R81 is hydrogen;
- X is C═O;
- and
- Y is NH.
14 more elements
A method for monitoring the response of a patient having a disease or condition characterized by amyloid deposit to a treatment, the method comprising
- (i) forming a detectable complex following the treatment by contacting an effective amount of a compound of the formula:
- or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition thereof, with a sample, a body part, or a body area of the patient;
- and
- (ii) detecting the formation of the detectable complex, wherein a decrease of detectable complex as compared to before the treatment indicates that the patient is responsive to the treatment;
- wherein the disease or condition is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body dementia, Down's syndrome, and Creutzfeldt-Jakob disease.
2 more elements
A method of detecting an amyloid or amyloid like protein, the method comprising
- (i) contacting the compound of formula (Ic), a pharmaceutically acceptable salt thereof, or a solvate thereof with a sample potentially comprising the amyloid or amyloid like protein, wherein in presence of an amyloid or amyloid like protein the compound forms a detectable complex;
- and
- (ii) detecting the formation of the detectable complex such that the presence or absence of the detectable complex correlates with the presence or absence of the amyloid or amyloid like protein;
- wherein the compound of Formula (Ic) is:
- wherein
- EDG is heterocycloalkyl of no more than 10 carbons optionally substituted with one or more R17;
- wherein 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 aryl 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 to 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;
- wherein the sample is from a patient having a disease or condition selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body dementia, Down's syndrome, and Creutzfeldt-Jakob disease.
20 more elements
Dependencies are inferred from the claim text.