Transthyretin stabilization

• US 20050261365A1
• Filed: 05/20/2005
• Published: 11/24/2005
• Est. Priority Date: 05/20/2004
• Status: Abandoned Application

• Current Assignee: The Scripps Research Institute
• Original Assignee: The Scripps Research Institute
• Inventors: Kelly, Jeffery W., Petrassi, H. Michael
• Application Number:
  US11/134,527
• Publication Number:
  US 20050261365A1
• Time in Patent Office: Days
• US Class Current: 514/468
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 229/42 with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
• CPC Class Codes: C07C 229/58 having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
• CPC Class Codes: C07C 229/60 with amino and carboxyl groups bound in meta- or para- positions
• CPC Class Codes: C07C 251/48 with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 39/367 polycyclic non-condensed, containing only six-membered aromatic rings as cyclic parts, e.g. halogenated poly-hydroxyphenylalkanes
• CPC Class Codes: C07C 65/24 polycyclic
• CPC Class Codes: C07D 307/91 Dibenzofurans; Hydrogenated dibenzofurans

Abstract

Dibenzofuran-4,6-dicarboxylic acid core structures having an aromatic substituent appended onto the at the C1 position using three different types of linkages are disclosed herein and shown to afford exceptional amyloidogenesis inhibitors that display increased affinity and greatly increased binding selectivity to TTR over all the other plasma proteins, relative to lead compound 1. It is further disclosed herein that these compounds function by imposing kinetic stabilization on the TTR tetramer.

Claims

1. A compound represented by Formula I:

wherein;

X is absent or is a diradical selected from the group consisting of —

O—

, —

S—

, and —

NH—

; and

R², R³, R⁴, and R⁵ are radicals independently selected from the group consisting of —

H, OH, —

F, —

Cl, —

Br, —

CF₃, and —

CO₂H.

2. A compound according to claim 1 represented by Formula II:

3. A compound according to claim 2 wherein:

R² is a radical selected from the group consisting of —

H, —

F, —

Cl, and —

CF₃.

4. A compound according to claim 2 wherein:

R⁴ is a radical selected from the group consisting of —

H, —

Cl, and —

CO₂H.

5. A compound according to claim 2 wherein:

R⁵ is a radical selected from the group consisting of —

H, —

F, and —

Cl.

6. A compound according to claim 2 selected from the group represented by the following structures:

7. A compound according to claim 1 represented by the following structure:

8. A compound according to claim 7 wherein:

R³ is a radical selected from the group consisting of —

H, —

F, —

Cl, —

Br, and —

CF₃.

9. A compound according to claim 7 wherein:

R⁵ is a radical selected from the group consisting of —

H, —

F, —

Cl, and —

Br.

10. A compound according to claim 7 selected from the group represented by the following structures:

11. A compound according to claim 1 represented by the following structure:

12. A compound according to claim 11 wherein:

R² is a radical selected from the group consisting of —

H, —

F, and —

Cl.

13. A compound according to claim 11 wherein:

R³ is a radical selected from the group consisting of —

H, —

F, —

Cl, —

CF₃, and —

CO₂H.

14. A compound according to claim 11 wherein:

R⁴ is a radical selected from the group consisting of —

H, and —

CO₂H.

15. A compound according to claim 11 wherein:

R⁵ is a radical selected from the group consisting of —

H, —

F, —

Cl, and —

CF₃.

16. A compound according to claim 11 selected from the group represented by the following structures:

17. A process comprising the step of contacting transthyretin with a concentration of a compound selected from claims 1-16 sufficient for inhibiting amyloid fibril formation.