US 8,940,918 B2Granted

Amyloid binding agents

AssigneeThe Regents of the University of California

InventorsJerry Yang, Emmanuel A. Theodorakis

Life of this patent

Estimating the term…

Abstract

There are provided compounds and methods for the detection of amyloids and treatment of diseases related to amyloids including Alzheimer's disease and other related amyloid-based neurodegenerative diseases.

Drawings

Claims15

Dependent claims

A compound having the structure of Formula (I),

wherein
EDG is an electron donor group;
πCE is a pi-conjugation element;
and
WSG is a water soluble group;
wherein
said electron donor group is R1-substituted or unsubstituted alkyl, R1-substituted or unsubstituted cycloalkyl, R1-substituted or unsubstituted heterocycloalkyl, R1-substituted or unsubstituted aryl, R1-substituted or unsubstituted heteroaryl, -NR4C(O)R3, -NR4R5, or -PR7R8,
wherein
R1 is halogen, -OR9, -NR10R11, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl
R4 is hydrogen, R12-substituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl R12-substituted or unsubstituted aryl or R12-substituted or unsubstituted heteroaryl;
R3, R5, R6, R7 and R8 are independently hydrogen, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl or R12-substituted or unsubstituted heteroaryl, wherein R4 and R5 are optionally joined together to form an R12-substituted or unsubstituted heterocycloalkyl, or R12-substituted or unsubstituted heteroaryl;
R9, R10 and R11 are independently hydrogen, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl, wherein R10 and R11 are optionally joined together to form an R12-substituted or unsubstituted heterocycloalkyl, or R12-substituted or unsubstituted heteroaryl
R12 is halogen, -OR13, -NR14R15, R16-substituted or unsubstituted alkyl, R16-substituted or unsubstituted heteroalkyl, R16-substituted or unsubstituted cycloalkyl, R16-substituted or unsubstituted heterocycloalkyl, R16-substituted or unsubstituted aryl, or R16-substituted or unsubstituted heteroaryl;
R13, R14 and R15 are independently hydrogen or unsubstituted alkyl;
and
R16 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
wherein
said pi-conjugation element has the formula:
-L1-(A1)q-L2-(A2)r-L3- or -L1-(A1)q-L4-A3-L2-(A2)r-L3-,
wherein
q and r are independently 0 or 1 and at least one of q or r is 1;
at least one of A1 or A2 is R17-substituted or unsubstituted
L1, L2, L3 and L4 are independently a bond or a linking group having the formula:
wherein x is an integer from 1 to 50;
A1, A2 and A3 are independently R17-substituted or unsubstituted arylene, or
R17-substituted or unsubstituted heteroarylene;
R17 is halogen, —OR18, —NR19R20, R21-substituted or unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl;
R18, R19 and R20 are independently hydrogen, R21-substituted or unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl;
R21 is halogen, —OR22, —NR23R24, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
and
R22, R23 and R24 are independently hydrogen or unsubstituted alkyl.

28 more elements

A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof,
wherein:
R4 and R5 are independently hydrogen, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl or R12-substituted or unsubstituted heteroaryl, wherein R4 and R5 are optionally joined together to form an R12-substituted or unsubstituted heterocycloalkyl, or R12-substituted or unsubstituted heteroaryl;
R12 is halogen, —OR13, —NR14R15, R16-substituted or unsubstituted alkyl, R16-substituted or unsubstituted heteroalkyl, R16-substituted or unsubstituted cycloalkyl, R16-substituted or unsubstituted heterocycloalkyl, R16-substituted or unsubstituted aryl, or R16-substituted or unsubstituted heteroaryl;
R13, R14 and R15 are independently hydrogen or unsubstituted alkyl;
R16 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
R17 is halogen, —OR18, —NR19R20, R21-substituted or unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl;
R18, R19 and R20 are independently hydrogen, R21-substituted or unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl;
R21 is halogen, —OR22, —NR23R24, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
R22, R23 and R24 are independently hydrogen or unsubstituted alkyl;
R29 is halogen, —OR30, —NR31R32, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
R30, R31 and R32 are independently hydrogen or unsubstituted alkyl;
y is an integer from 1 to 10;
and
z is an integer from 0 to 6.

12 more elements

Dependencies are inferred from the claim text.

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US 8,940,918 B2Granted

Amyloid binding agents

AssigneeThe Regents of the University of California

InventorsJerry Yang, Emmanuel A. Theodorakis

Life of this patent

About 4 years 1 month of term left · ends 10 Dec 2030 (estimated)

Priority10 Dec 2009

Filed10 Dec 2010

Published29 Nov 2012

Granted27 Jan 2015

Today12 Oct 2026

Term ends10 Dec 2030

Priority10 Dec 2009

Granted27 Jan 2015

Term ends10 Dec 2030

Life of this patent

Estimating the term…

Abstract

Drawings

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Drawings

Claims15

Dependent claims

A compound having the structure of Formula (I),

wherein
EDG is an electron donor group;
πCE is a pi-conjugation element;
and
WSG is a water soluble group;
wherein
said electron donor group is R1-substituted or unsubstituted alkyl, R1-substituted or unsubstituted cycloalkyl, R1-substituted or unsubstituted heterocycloalkyl, R1-substituted or unsubstituted aryl, R1-substituted or unsubstituted heteroaryl, -NR4C(O)R3, -NR4R5, or -PR7R8,
wherein
R1 is halogen, -OR9, -NR10R11, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl
R4 is hydrogen, R12-substituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl R12-substituted or unsubstituted aryl or R12-substituted or unsubstituted heteroaryl;
R3, R5, R6, R7 and R8 are independently hydrogen, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl or R12-substituted or unsubstituted heteroaryl, wherein R4 and R5 are optionally joined together to form an R12-substituted or unsubstituted heterocycloalkyl, or R12-substituted or unsubstituted heteroaryl;
R9, R10 and R11 are independently hydrogen, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl, wherein R10 and R11 are optionally joined together to form an R12-substituted or unsubstituted heterocycloalkyl, or R12-substituted or unsubstituted heteroaryl
R12 is halogen, -OR13, -NR14R15, R16-substituted or unsubstituted alkyl, R16-substituted or unsubstituted heteroalkyl, R16-substituted or unsubstituted cycloalkyl, R16-substituted or unsubstituted heterocycloalkyl, R16-substituted or unsubstituted aryl, or R16-substituted or unsubstituted heteroaryl;
R13, R14 and R15 are independently hydrogen or unsubstituted alkyl;
and
R16 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
wherein
said pi-conjugation element has the formula:
-L1-(A1)q-L2-(A2)r-L3- or -L1-(A1)q-L4-A3-L2-(A2)r-L3-,
wherein
q and r are independently 0 or 1 and at least one of q or r is 1;
at least one of A1 or A2 is R17-substituted or unsubstituted
L1, L2, L3 and L4 are independently a bond or a linking group having the formula:
wherein x is an integer from 1 to 50;
A1, A2 and A3 are independently R17-substituted or unsubstituted arylene, or
R17-substituted or unsubstituted heteroarylene;
R17 is halogen, —OR18, —NR19R20, R21-substituted or unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl;
R18, R19 and R20 are independently hydrogen, R21-substituted or unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl;
R21 is halogen, —OR22, —NR23R24, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
and
R22, R23 and R24 are independently hydrogen or unsubstituted alkyl.

28 more elements

A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof,
wherein:
R4 and R5 are independently hydrogen, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl or R12-substituted or unsubstituted heteroaryl, wherein R4 and R5 are optionally joined together to form an R12-substituted or unsubstituted heterocycloalkyl, or R12-substituted or unsubstituted heteroaryl;
R12 is halogen, —OR13, —NR14R15, R16-substituted or unsubstituted alkyl, R16-substituted or unsubstituted heteroalkyl, R16-substituted or unsubstituted cycloalkyl, R16-substituted or unsubstituted heterocycloalkyl, R16-substituted or unsubstituted aryl, or R16-substituted or unsubstituted heteroaryl;
R13, R14 and R15 are independently hydrogen or unsubstituted alkyl;
R16 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
R17 is halogen, —OR18, —NR19R20, R21-substituted or unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl;
R18, R19 and R20 are independently hydrogen, R21-substituted or unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl;
R21 is halogen, —OR22, —NR23R24, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
R22, R23 and R24 are independently hydrogen or unsubstituted alkyl;
R29 is halogen, —OR30, —NR31R32, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
R30, R31 and R32 are independently hydrogen or unsubstituted alkyl;
y is an integer from 1 to 10;
and
z is an integer from 0 to 6.

12 more elements

Dependencies are inferred from the claim text.

Description19,268 words

Summary535 words

#This application is a national phase application of PCT/US2010/059952, filed Dec. 10, 2010, which claims priority to U.S. Application No. 61/285,470, filed Dec. 10, 2009, the entire contents of which are incorporated herein by reference.

#Alzheimer's disease (AD) is characterized by a progressive loss of cognitive function and constitutes the most common and fatal neurodegenerative disorder. Genetic and clinical evidence supports the hypothesis that accumulation of amyloid deposits in the brain plays an important role in the pathology of the disease. This event is associated with perturbations of biological functions in the surrounding tissue leading to neuronal cell death, thus contributing to the disease process. The deposits are composed primarily of amyloid (Aβ) peptides, typically a 39-43 amino acid sequence that self aggregates into a fibrillar β-pleated sheet motif. While the exact three-dimensional structure of the aggregated Aβ peptides is not known, a model structure that sustains the property of aggregation has been proposed. This creates opportunities for in vivo imaging of amyloid deposits that not only can help evaluate the time course and evolution of the disease but can also allow the timely monitoring of therapeutic treatments.

#Historically, Congo Red (CR) and Thioflavin T (ThT) have provided the starting point for the visualization of amyloid plaques and are still commonly employed in post mortem histological analyses. However, due to their charge these compounds are thought to be unsuitable for in vivo applications. To address this issue, several laboratories developed compounds with non charged, lipophilic (log P=0.1-3.5) and low molecular weight chemical structures (M.W. less than 650) that facilitate crossing of the blood brain barrier. Further functionalization of these compounds with radio-nuclides led to a new generation of in vivo diagnostic reagents that target plaques and related structures for imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT), as known in the art.

Brief description of the drawings11 figures

#FIGS. 1A-D depict fluorescence excitation and emission spectra of Cmpds 8d and 11 in aqueous PBS solution (solid lines) and in the presence of Aβ peptide (dashed lined). FIG. 1A: fluorescence excitation spectrum of Cmpd 8d. FIG. 1B: emission spectrum of Cmpd 8d. FIG. 1C: fluorescence excitation spectrum of Cmpd 11. FIG. 1D: emission spectrum of Cmpd 11.

#FIG. 2 depicts the apparent binding constant (Kd) of Cmpds 8d and 11 to preaggregated Aβ peptide. Legend: Cmpd 8d (diamond); Cmpd 11 (box).

#FIG. 3 depicts the inhibition of IgG-Aβ fibril interactions with Cmpd 8d (FIG. 3 top) and Cmpd 11 (FIG. 3 bottom).

Detailed description18,387 words

#The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

#Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., —CH2O— is equivalent to —OCH2—.

#The term “electron donating group (EDG)” refers to a chemical moiety that modifies the electrostatic forces acting on a nearby chemical moiety by donating negative charge to that chemical moiety. In some embodiments, the electron donating group donates negative charge to the π-conjugation element of the compounds disclosed herein.

Facts

Application: 13/515,239Filed 10 Dec 2010 · us provisional application
Priority: 10 Dec 2009
Published: US 2012/0302603 A129 Nov 2012
Granted: 27 Jan 2015
Term ends: 10 Dec 2030
Estimated · howhide
20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.

Classification16 codes

G01N 33/6896
Related to diseases not provided for elsewhere: neurological disorders, e.g. Alzheimer's disease
A61P 21/02
Drugs for disorders of the muscular or neuromuscular system: muscle relaxants, e.g. for tetanus or cramps
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/14
Drugs for disorders of the nervous system: for treating abnormal movements, e.g. chorea, dyskinesia

Family

Application61/285,470Us provisional application · filed 10 Dec 2009
US 2012/0302603 A1Pre-grant publication · published 29 Nov 2012
US 8,940,918 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

10 Dec 2009Priority claimedParent application 61/285,470
10 Dec 2010Application filedUS 13/515,239
5 Oct 2012Assigned to The Regents of the University of Californiaassignment of assignor's interest
29 Nov 2012PublishedUS 2012/0302603 A1
27 Jan 2015GrantedUS 8,940,918 B2
3 Aug 2015Assigned to National Institutes of Health (Nih), U.S. Dept. of Health and Human Services (Dhhs), U.S. Governmentconfirmatory license
12 Oct 2026TodayWithin its term
10 Dec 2030Term endsEstimated

Citations

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