Methods of treating disorders associated with protein aggregation

Patent metadata

Field	Value
Publication number	US-9820990-B2
Application number	US-201615247518-A
Country	US
Kind code	B2
Filing date	Aug 25, 2016
Priority date	Nov 5, 2009
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

The present invention relates to methods of treatment of clinical disorders associated with protein aggregation comprising administering, to a subject, an effective amount of an anti-protein aggregate (“APA”) compound selected from the group consisting of pimozide, fluphenazine (e.g., fluphenazine hydrochloride), tamoxifen (e.g., tamoxifen citrate), taxol, cantharidin, cantharidic acid, salts thereof and their structurally related compounds. It is based, at least in part, on the discovery that each of the aforelisted compounds were able to promote degradation of aggregated ATZ protein in a Caenorhabditis elegans model system. According to the invention, treatment with one or more of these APA compounds may be used to ameliorate the symptoms and signs of AT deficiency as well as other disorders marked by protein aggregation, including, but not limited to, Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease.

First claim

The invention claimed is:

1. A method of treating traumatic brain injury comprising administering, to a subject in need of such treatment, a compound selected from the group consisting of 2-(trifluoromethyl)-10-[3-(diethanolamino)-2-hydroxypropyl]phenothiazine, fluphenazine-4-chlorophenoxy-isobutyrate ester, 2-nitro-10-[3-[4-(2-hydroxyethyl)-1-piperazinyl]propyl]phenothiazine, 2-(2,2-dicyanoethenyl)-10-[3-[3-[4-(2-hydroxyethyl)-1-piperazinyl [propyl]phenothiazine, 2-(2-nitro-ethenyl)-10-[3-[4-(2-hydroxyethyl)-1-piperazinyl [propyl]phenothiazine, and 10-[3-[4-(2-hydroxyethyl)-1-piperazinyl [propyl]phenothiazine-2-carbonitrile, in an amount and dosing regimen that inhibits progression of the traumatic brain injury.

2. A method of treating traumatic brain injury comprising administering, to a subject in need of such treatment, a compound selected from the group consisting of 1-[2-[4-[3-[2-(Trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-1-piperazinyl]ethyl]pyridinium p-Toluenesulfonate and compounds, wherein the hydroxyethyl group of fluphenazine (R═CH 2 CH 2 OH) is replaced by R═CH 3 , R═CH 2 CH 2 OCH 2 CH 2 OH, R═OCH 2 CH 3 , R═O(CH 2 ) 3 CH 3 , R═OCH 2 CH 2 OCH 3 , R═OCH 2 CH═CH 2 , R═OCH(C 2 H 5 ) 2 , R═O(CH 2 ) 5 CH 3 , R═OC 6 H 5 , R═NHCH 2 CH 2 OH, R═NHCH 2 CH 2 OCH 3 , R═NHCH 2 CH═CH 2 , R═N(CH 2 CH═CH 2 ) 2 , R═

R═

and R═NHN(CH 3 ) 2 , in an amount and dosing regimen that inhibits progression of the traumatic brain injury.

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education
• The Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Pak Stephen C
• Perlmutter David Hirsch
• Silverman Gary A

Classifications

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• A61K31/138

  Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377) · CPC title

• A61P25/28

  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 title

• A01K2217/052

  inducing gain of function · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title