Methods and compositions for treating amyloid-related diseases

• US 20050038117A1
• Filed: 06/18/2004
• Published: 02/17/2005
• Est. Priority Date: 06/23/2003
• Status: Active Grant

• Current Assignee: Bellus Health (Interational) Limited, Queen's University At Kingston
• Original Assignee: Neurochem Incorporated, Neurochem (International) Limited, Queen's University At Kingston
• Inventors: Kong, Xianqi, Szarek, Walter A., Gervais, Francine
• Granted Patent: US 7,244,764 B2
• Time in Patent Office: Days
• US Class Current: 514/554
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/18 with a ring being at least seven-membered
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2602/42 the bicyclo ring system containing seven carbon atoms
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 307/02 Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
• CPC Class Codes: C07C 309/13 containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
• CPC Class Codes: C07C 309/14 containing amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 309/15 the nitrogen atom of at least one of the amino groups being part of any of the groups , X being a hetero atom, Y being any atom
• CPC Class Codes: C07C 309/46 having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
• CPC Class Codes: C07C 309/69 of a carbon skeleton substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07C 311/32 : of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 311/46 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 335/32 : having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
• CPC Class Codes: C07C 381/02 : Thiosulfates
• CPC Class Codes: C07D 295/084 : with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/088 : to an acyclic saturated chain
• CPC Class Codes: C07F 9/1651 : with hydroxyalkyl compounds with further substituents on alkyl
• CPC Class Codes: C07F 9/2458 : of aliphatic amines

Abstract

Methods, compounds, pharmaceutical compositions and kits are described for treating or preventing amyloid- +related disease.

Claims

1. A compound of Formula I:

3. The compound of claim 1 or 2, wherein R² is hydrogen.

4. The compound of claim 1 or 2, wherein R¹ is straight chain alkyl.

5. The compound of claim 4, wherein R¹ is ethyl, n-pentyl, n-heptyl, n-octyl, or n-nonyl.

6. The compound of claim 1 or 2, wherein R¹ is t-butyl.

7. The compound of claim 1 or 2, wherein R¹ is carbocyclic.

8. The compound of claim 1 or 2, wherein R¹ is C₇-C₁₀ bicycloalkyl.

9. The compound of claim 1 or 2, wherein R¹ is tricycloalkyl.

10. The compound of claim 9, wherein R¹ is tricyclo[3.3.1.0^3,7]decyl or adamantyl.

11. The compound of claim 9, wherein R¹ is bicyclo[2.1.2]heptyl.

12. The compound of claim 1 or 2, wherein said bicyclic fused ring group is indolyl.

13. The compound of claim 1 or 2, wherein L¹ is CH₂CH₂.

14. The compound of claim 1 or 2, wherein R¹ is tetrahydronaphthyl.

15. The compound of claim 1 or 2, wherein L¹ is absent.

16. The compound of claim 1 or 2, wherein said compound is:

58. A kit for use in treating amyloid related disease comprising a compound of claim 1, and instructions for use in the method of the instant invention.

59. A method of treating or preventing an amyloid-related disease in a subject comprising administering to a subject in need thereof a compound of claim 1 or depicted in the Tables and Figures in an amount effective to treat or prevent an amyloid related disease.

60. The method according to claim 59, wherein said amyloid-related disease is Alzheimer'"'"'s disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, MCI, or Down'"'"'s syndrome.

61. The method according to claim 59, wherein amyloid fibril formation or deposition, neurodegeneration, or cellular toxicity is reduced or inhibited upon administration of said compound.

62. The method according to claim 59, wherein said amyloid-related disease is diabetes, AA amyloidosis, AL amyloidosis, or hemodialysis related amyloidosis (β

₂M).

63. The method according to claim 59, wherein said subject is a human.

64. The method according to claim 59, wherein said subject has Alzheimer'"'"'s disease, Mild Cognitive Impairment, or cerebral amyloid angiopathy, and stabilization of cognitive function, prevention of a further decrease in cognitive function, or prevention, slowing, or stopping of disease progression occurs in said patient upon administration.

65. A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a therapeutic compound of claim 1 or depicted in the Tables and Figures or a pharmaceutically acceptable salt thereof, such that said therapeutic compound inhibits an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to inhibit amyloid deposition.

66. A method for inhibiting amyloid deposition in a subject comprising orally administering to said subject an effective amount of a therapeutic compound of claim 1 or depicted in the Tables and Figures or a pharmaceutically acceptable salt thereof.

67. A method for reducing amyloid deposits in a subject having amyloid deposits, the method comprising administering to said subject an effective amount of a therapeutic compound of claim 1 or depicted in the Tables and Figures, or pharmaceutically acceptable salts thereof.

68. The method according to claim 59, wherein the therapeutic compound is administered orally.

69. The method according to claim 59, wherein said therapeutic compound is administered in a pharmaceutically acceptable vehicle.

70. A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a therapeutic compound of claim 1 or depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof, such that amyloid deposition is inhibited.

71. The method of claim 70, wherein the therapeutic compound is administered orally.

72. The method of claim 70, wherein said therapeutic compound is administered in a pharmaceutically acceptable vehicle.

73. A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a compound of claim 1 or depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof, such that the biodistribution of the compound for an intended target site is not prevented while maintaining activity of the compound, such that amyloid deposition is inhibited.

75. A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a compound of claim 1 or depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof, such that the compound inhibits an interaction between an amyloidogenic protein and a constituent of a basement membrane and amyloid deposition is inhibited.

76. A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a compound of claim 1 or depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof, such that an interaction between an amyloidogenic protein and a constituent of a basement membrane is inhibited and amyloid deposition is inhibited.

77. A method for reducing amyloid deposits in a subject having amyloid deposits, the method comprising administering to a subject an effective amount of a compound of claim 1 or depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof, such that amyloid deposits are reduced in the subject.

78. A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a compound of claim 1 or depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof, such that the compound inhibits an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane, such that amyloid deposition is inhibited.

79. The use of a compound according to claim 59 in the preparation of a medicament for the treatment or prevention of an amyloid-related disease.

80. A pharmaceutical composition for the treatment or prevention of an amyloid-related disease comprising a compound according to claim 1.

81. A pharmaceutical composition comprising a compound according to claim 1.

83. A pharmaceutical composition for treating amyloidosis comprising a compound, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit amyloid deposition in a subject, the compound wherein in the compound is of claim 1.

84. A pharmaceutical composition for treating amyloidosis comprising a compound, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit an interaction between an amyloidogenic protein and a constituent of a basement membrane and to inhibit amyloid deposition in a subject, wherein in the compound is of claim 1.

85. A pharmaceutical composition for preventing amyloidosis comprising a compound, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit an interaction between an amyloidogenic protein and a constituent of a basement membrane and to inhibit amyloid deposition in a subject, wherein in the compound is of claim 1.

86. A pharmaceutical composition for treating amyloidosis comprising a compound, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit amyloid deposition in a subject, wherein in the compound is of claim 1.

87. The method of claim 59, wherein said compound prevents or inhibits amyloid fibril formation.

88. The method of claim 59, wherein said compound prevents amyloid peptide, in its soluble, oligomeric form or in its fibrillar form, from binding or adhering to a cell surface and causing cell damage or toxicity.

89. The method of claim 59, wherein said compound blocks amyloid-induced cellular toxicity or microglial activation.

90. The method of claim 59, wherein said compound blocks amyloid-induced neurotoxicity.

91. The method of claim 59, wherein said compound reduces the rate or amount of amyloid aggregation, fibril formation, or deposition.

92. The method of claim 59, wherein said compound slows the rate of amyloid fibril formation or deposition.

93. The method of claim 59, wherein said compound lessens the degree of amyloid deposition.

94. The method of claim 59, wherein said compound inhibits, reduces, or prevents amyloid fibril formation.

95. The method of claim 59, wherein said compound inhibits amyloid induced inflammation.

96. The method of claim 59, wherein said compound enhances the clearance of amyloid from the brain.

97. The method of claim 59, wherein said compound alters the equilibrium of amyloid between the CSF or brain and the plasma and decreases the amount of amyloid-β

in the brain versus the equilibrium distribution in an untreated subject.

98. The method of claim 59, wherein said compound reverses deposition of amyloid in a subject having amyloid deposits.

99. The method of claim 59, wherein said compound favors deposition of amyloid in a subject having amyloid deposits.

100. The method of claim 59, wherein said compound favors plaque clearance or slows deposition in a subject having amyloid deposits.

101. The method of claim 59, wherein said compound decreases the amyloid concentration in the brain of a subject versus an untreated subject.

102. The method of claim 59, wherein said compound penetrates into the brain.

103. The method of claim 59, wherein said compound maintains soluble amyloid in a non-fibrillar form.

104. The method of claim 59, wherein said compound increases the rate of clearance of soluble amyloid from the brain of a subject versus an untreated subject.

105. The method of claim 59, wherein said compound inhibits or reduces an interaction between amyloid and a cell surface constituent.

106. The method of claim 105, wherein said cell surface constituent is a glycosaminoglycan or proteoglycan constituent of a basement membrane.

107. The method of claim 59, wherein said amyloid is an amyloid-β

peptide having 39-43 amino-acids.

108. The method of claim 59, wherein said amyloid is an amyloidogenic peptide produced from PAPP.

109. The method of claim 59, wherein said amyloid-related disease is Mild Cognitive Impairment or Mild-to-Moderate Cognitive Impairment.

110. The method of claim 59, wherein said amyloid-related disease is vascular dementia.

111. The method of claim 59, wherein said amyloid-related disease is Alzheimer'"'"'s disease.

112. The method of claim 111, wherein said Alzheimer'"'"'s disease is sporadic (non-hereditary) Alzheimer'"'"'s disease, familial (hereditary) Alzheimer'"'"'s disease, or early Alzheimer'"'"'s disease.

113. The method of claim 59, wherein said amyloid-related disease is β

₂M amyloidosis, AL amyloidosis, AA amyloidosis, or diabetes.

114. The method of claim 59, wherein said amyloid-related disease is cerebral amyloid angiopathy or hereditary cerebral hemorrhage.

115. The method of claim 59, wherein said amyloid-related disease is senile dementia, Down'"'"'s syndrome, inclusion body myositis, or age-related macular degeneration.

116. The method of claim 59, wherein said amyloid-related disease is familial amyloid polyneuropathy (FAP), senile systemic amyloidosis, Tenosynovium, familial amyloidosis, Ostertag-type, non-neuropathic amyloidosis, cranial neuropathy, hereditary cerebral hemorrhage, familial dementia, chronic dialysis, familial Creutzfeldt-Jakob disease;

Gerstmann-Strä

ussler-Scheinker syndrome, hereditary spongiform encephalopathies, prion diseases, familial Mediterranean fever, Muckle-Well'"'"'s syndrome, nephropathy, deafniess, urticaria, limb pain, cardiomyopathy, cutaneous deposits, multiple myeloma, benign monoclonal gammopathy, maccoglobulinaemia, myeloma associated amyloidosis, medullary carcinomas of the thyroid, isolated atrial amyloid, or diabetes.

117. The method of claim 59, wherein said pharmaceutical composition is therapeutically or prophylactically administered to a subject.

118. The method of claim 59, wherein said pharmaceutical composition is orally administered to a subject.

119. The method of claim 59, wherein said subject is a human.

120. The method of claim 59, wherein said subject is a human over 40 years old.

121. The method of claim 59, wherein said subject is a human over 50 years old.

122. The method of claim 59, wherein said subject is a human over 60 years old.

123. The method of claim 59, wherein said subject is a human over 70 years old.

124. The method of claim 59, wherein said subject is a human over 80 years old.

125. The method of claim 59, wherein said subject is a human over 85 years old.

126. The method of claim 59, wherein said subject is a female human.

127. The method of claim 59, wherein said subject is a postmenopausal female human.

128. The method of claim 59, wherein said subject is on hormone replacement therapy.

129. The method of claim 59, wherein said subject is a male human.

130. The method of claim 59, wherein said subject has Alzheimer'"'"'s disease or a genetic predisposition for developing Alzheimer'"'"'s disease.

131. The method of claim 59, wherein said subject has vascular dementia.

132. The method of claim 59, wherein said subject has senile dementia.

133. The method of claim 59, wherein said subject has Mild Cognitive Impairment.

134. The method of claim 59, wherein said subject has a genomic mutation in the APP gene.

135. The method of claim 59, wherein said subject is a carrier of the ApoE₂ allele.

136. The method of claim 59, wherein said subject has a genomic mutation in a presenilin gene.

137. The method of claim 59, wherein said subject has familial, sporadic, or idiopathic Alzheimer'"'"'s disease or cerebral amyloid angiopathy.

138. The method of claim 59, wherein said subject has amyloid deposits.

139. The method of claim 59, wherein said subject'"'"'s brain has amyloid-β

amyloid deposits.

140. The pharmaceutical composition of claim 83, wherein said compound prevents or inhibits amyloid fibril formation.

141. The pharmaceutical composition of claim 83, wherein said compound prevents amyloid peptide, in its soluble, oligomeric form or in its fibrillar form, from binding or adhering to a cell surface and causing cell damage or toxicity.

142. The pharmaceutical composition of claim 83, wherein said compound blocks amyloid-induced cellular toxicity or microglial activation.

143. The pharmaceutical composition of claim 83, wherein said compound blocks amyloid-induced neurotoxicity.

144. The pharmaceutical composition of claim 83, wherein said compound reduces the rate or amount of amyloid aggregation, fibril formation, or deposition.

145. The pharmaceutical composition of claim 83, wherein said compound slows the rate of amyloid fibril formation or deposition.

146. The pharmaceutical composition of claim 83, wherein said compound lessens the degree of amyloid deposition.

147. The pharmaceutical composition of claim 83, wherein said compound inhibits, reduces, or prevents amyloid fibril formation.

148. The pharmaceutical composition of claim 83, wherein said compound inhibits amyloid-induced inflammation.

149. The pharmaceutical composition of claim 83, wherein said compound enhances the clearance of amyloid from the brain.

150. The pharmaceutical composition of claim 83, wherein said compound alters the equilibrium of amyloid between the brain and the plasma and decreases the amount of amyloid in the brain versus the equilibrium distribution in an untreated subject.

151. The pharmaceutical composition of claim 83, wherein said compound reverses or favors deposition of amyloid in a subject having amyloid deposits.

152. The pharmaceutical composition of claim 83, wherein said compound favors plaque clearance or slows deposition in a subject having amyloid deposits.

153. The pharmaceutical composition of claim 83, wherein said compound decreases the amyloid concentration in the brain of a subject versus an untreated subject.

154. The pharmaceutical composition of claim 83, wherein said compound penetrates into the brain.

155. The pharmaceutical composition of claim 83, wherein said compound maintains soluble amyloid in a non-fibrillar form.

156. The pharmaceutical composition of claim 83, wherein said compound increases the rate of clearance of soluble amyloid from the CSF or brain of a subject versus an untreated subject.

157. The pharmaceutical composition of claim 83, wherein said compound inhibits or reduces an interaction between amyloid-β

and a cell surface constituent.

158. The pharmaceutical composition of claim 157, wherein said cell surface constituent is a glycosaminoglycan or proteoglycan constituent of a basement membrane.

159. The pharmaceutical composition of claim 83, wherein said amyloid-β

is a peptide having 39-43 amino-acids.

160. The pharmaceutical composition of claim 83, wherein said amyloid-β

is an amyloidogenic peptide produced from β

APP.

161. The pharmaceutical composition of claim 83, wherein said amyloid-related disease is Mild Cognitive Impairment or Mild-to-Moderate Cognitive Impairment.

162. The pharmaceutical composition of claim 83, wherein said amyloid-related disease is vascular dementia.

163. The pharmaceutical composition of claim 83, wherein said amyloid-related disease is Alzheimer'"'"'s disease.

164. The pharmaceutical composition of claim 163, wherein said Alzheimer'"'"'s disease is sporadic (non-hereditary) Alzheimer'"'"'s disease, early Alzheimer'"'"'s disease, or familial (hereditary) Alzheimer'"'"'s disease.

165. The pharmaceutical composition of claim 83, wherein said amyloid-related disease is AA amyloidosis, AL amyloidosis, β

₂M amyloidosis, or diabetes.

166. The pharmaceutical composition of claim 83, wherein said amyloid-related disease is cerebral amyloid angiopathy or hereditary cerebral hemorrhage.

167. The pharmaceutical composition of claim 83, wherein said amyloid-related disease is senile dementia, Down'"'"'s syndrome, Mild Cognitive Impairment, inclusion body myositis, or age-related macular degeneration.

168. The pharmaceutical composition of claim 83, wherein said amyloid-related disease is familial amyloid polyneuropathy (FAP), senile systemic amyloidosis, familial amyloidosis, Ostertag-type, non-neuropathic amyloidosis, cranial neuropathy, hereditary cerebral hemorrhage, familial dementia, chronic dialysis, familial Creutzfeldt-Jakob disease;

Gerstmann-Strä

ussler-Scheinker syndrome, hereditary spongiform encephalopathies, prion diseases, familial Mediterranean fever, Muckle-Well'"'"'s syndrome, nephropathy, deafness, urticaria, limb pain, cardiomyopathy, cutaneous deposits, multiple myeloma, benign monoclonal gammopathy, maccoglobulinaemia, myeloma associated amyloidosis, medullary carcinomas of the thyroid, isolated atrial amyloid, or diabetes.

169. The pharmaceutical composition of claim 83, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable acid, base, buffering agent, inorganic salt, solvent, or preservative.

170. The pharmaceutical composition of claim 83, further comprising a compound that increases the cerebral bioavailability of said compound.

171. The pharmaceutical composition of claim 83, wherein said compound is dissolved in a liquid pharmaceutically acceptable vehicle.

172. The pharmaceutical composition of claim 83, wherein said compound is present as a homogenous mixture in a capsule or pill.

173. The method of claim 59, wherein the deposition in a subject of amyloid protein is reduced by at least 15%.

174. The method of claim 59, wherein the deposition in a subject of amyloid protein is reduced by at least 40%.

175. The method of claim 59, wherein the deposition in a subject of amyloid protein is reduced by at least 60%.

176. The method of claim 59, wherein the deposition in a subject of amyloid protein is reduced by at least 80%.

177. A method for inhibiting amyloid deposition in a subject comprising contacting a body fluid with a compound of claim 1 or depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof, and administering said body fluid to said subject, such that amyloid deposition in said subject is inhibited.

178. The method of claim 177, wherein said body fluid is blood.

179. The method of claim 177, wherein said body fluid is in contact with said compound ex vivo.

180. The method of claim 179, wherein said subject is suffering from hemodialysis related amyloidosis.

181. The method of claim 59, wherein said amyloid-related disease is diabetes, wherein glycemia is stablized.

182. The method of claim 59, wherein said amyloid-related disease is diabetes, wherein β

cell mass loss is prevented or reduced.

183. The method of claim 59, wherein said amyloid-related disease is diabetes, wherein hyperglycemia due to β

cell mass loss is reduced.

184. The method of claim 59, wherein said amyloid-related disease is diabetes, wherein the change of the pro-IAPP/IAPP ratio is stabilized.

185. The method of claim 59, wherein said amyloid-related disease is diabetes, wherein insulin production is modulated.

186. The method of claim 185, wherein insulin production is stabilized or increased.

187. The method of claim 59, related to β

₂M, wherein accumulation of fibrils in a joint of said subject is prevented or reduced.

188. The method of claim 59, wherein said amyloid related disease is treated or prevented by reducing or preventing inflammation.

189. A method for preventing, slowing, or stopping disease progression comprising administering to a subject an effective amount of a compound of claim 1, such that said disease progression is prevented slowed, or stopped.

190. The method of claim 189, wherein said disease is Mild Cognitive Impairment, Mild-to-Moderate Cognitive Impairment, vascular dementia, Alzheimer'"'"'s disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, senile dementia, Down'"'"'s syndrome, inclusion body myositis, or age-related macular degeneration.

191. A method for treating a subject for an amyloid-related disease, comprising:

administering a cognitive test to a subject prior to administration of a compound of claim 1;

administering an effective amount of the compound to the subject, and

administering a cognitive test to the subject subsequent to administration of said compound, such that said subject is treated for said amyloid-related disease, wherein the subject'"'"'s score on said cognitive test is improved.

192. The method of claim 191, wherein said cognitive test is CDR, MMSE, or ADAS-Cog.

193. The method of claim 191, wherein the subject'"'"'s score is maintained.

194. The method of claim 191, wherein said cognitive test is CDR or ADAS-Cog, wherein said subject'"'"'s score is decreased.

195. The method of claim 191, wherein said cognitive test is MMSE, wherein the subject'"'"'s score is increased.

196. The method of claim 192, wherein the rate of increase of the subject'"'"'s score on CDR, or ADAS-Cog, is less than that of untreated controls.

197. The method of claim 192, wherein the rate of decrease of the subject'"'"'s score on MMSE, is less than that of untreated controls.

198. The method of claim 191, wherein said amyloid related disease is Mild Cognitive Impairment, Mild-to-Moderate Cognitive Impairment, vascular dementia, Alzheimer'"'"'s disease, senile dementia, or Down'"'"'s syndrome.

199. The method of claim 59, wherein the amyloid protein is AH amyloid protein, AL amyloid protein, amyloid λ

, amyloid κ

, amyloid κ

IV, amyloid γ

, or amyloid γ

1.

200. A method for reducing or preventing the deposition of amyloid protein, comprising administering to a subject in need thereof a compound of claim 1, wherein said amyloid protein is AH amyloid protein, AL amyloid protein, amyloid λ

, amyloid κ

, amyloid κ

IV, amyloid γ

, or amyloid γ

1.

201. A method for reducing the rate of change of organ function due to amyloid deposition, comprising administering to a subject in need thereof a compound of claim 1 or depicted in the Tables or Figures, such that the rate of change of organ function to amyloid deposition is reduced.

202. A method for inhibiting fibril formation, comprising administering to a subject an effective amount of a compound of claim 1 or depicted in the Tables or Figures, wherein said effective amount is effective to inhibit protein-protein interactions, such that fibril formation is inhibited.

203. A method for treating CAA or hereditary cerebral hemorrhage, comprising administering an effective amount of a compound of claim 1 or depicted in the Tables or Figures, wherein said effective amount is effective to decrease the recurrence of hemorrhagic stroke.

2. A compound of Formula II:

17. A compound of Formula III:

18. The compound of claim 17, wherein n is 2, 3 or 4.

19. The compound of claim 17, wherein R¹¹ is a salt-forming cation.

20. The compound of claim 19, wherein said salt-forming cation is lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, or ammonium.

21. The compound of claim 17, wherein R¹¹ is an ester-forming group.

22. The compound of claim 21, wherein said ester-forming group is substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl.

23. The compound of claim 17, wherein R³ and R⁴ are taken together form a double bond.

24. The compound of claim 17, wherein R⁴, R⁵, R⁶, and R⁷ are each hydrogen.

25. The compound of claim 17, wherein R^A, R^B, R^C, R^D, and R^E are each hydrogen.

26. The compound of claim 17, wherein R¹¹ and A taken together are the residue of a natural or unnatural amino acid or a pharmaceutically acceptable salt or ester thereof.

27. The compound of claim 17, wherein m is 0 or 1.

28. The compound of claim 17, wherein m is 3.

29. The compound of claim 17 , wherein A is oxygen.

30. The compound of claim 17, wherein R³ is a moiety of Formula IIIa.

31. The compound of claim 17, wherein said compound is:

32. A compound of Formula IV:

33. The compound of claim 32, wherein m is 0.

34. The compound of claim 32, wherein n is 2, 3, or 4.

35. The compound of claim 32, wherein R⁴, R⁵, R⁶ and R⁷ are each hydrogen.

36. The compound of claim 32, wherein R⁸, R⁹, R¹⁰, and R¹² are each hydrogen.

37. The compound of claim 36, wherein said compound is:

38. A compound of Formula V:

39. The compound of claim 38, wherein n is 2, 3 or 4.

40. The compound of claim 38, wherein n is 3.

41. The compound of claim 38, wherein m is 0.

42. The compound of claim 38, wherein (aa)_m comprises a glycine residue.

43. The compound of claim 38, wherein R¹⁵ is hydrogen or substituted alkyl.

44. The compound of claim 38, wherein R¹⁵ is arylalkyl.

45. The compound of claim 38, wherein said compound is:

46. The compound of the Formula VI:

47. The compound of claim 46, wherein R¹¹ is a salt forming cation.

48. The compound of claim 46, wherein A is oxygen.

49. The compound of claim 46, wherein Y¹ is oxygen or sulfur, and R²² is absent.

50. The compound of claim 46, wherein said aromatic ring is pyridyl.

51. The compound of claim 46, wherein Y¹ is sulfur.

52. The compound of claim 46, wherein said compound is selected from the group consisting of:

53. A compound of the formula:

54. A compound of Formula I:

55. A compound of Formula II:

56. A compound of Formula II:

57. A compound of Formula II:

74. (Cancelled).

82. A pharmaceutical composition comprising a compound described in the Tables, Formulas or Schemes.