Substrate reduction therapy

• US 8,557,844 B2
• Filed: 06/26/2008
• Issued: 10/15/2013
• Est. Priority Date: 06/27/2007
• Status: Active Grant

• Current Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Original Assignee: United States Department Of Health And Human Services (Government of the United States of America), Chancellor Masters & Scholars of The University of Cambridge (University of Cambridge)
• Inventors: Platt, Frances Mary, Lloyd-Evans, Emyr, Porter, Forbes Dennison
• Primary Examiner(s): Jiang, Shaojia Anna
• Assistant Examiner(s): Lau, Jonathan S
• Application Number:
  US12/666,279
• Publication Number:
  US 20100204162A1
• Time in Patent Office: 1,937 Days
• Field of Search: 514/27, 514/315
• US Class Current: 514/315
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/431 containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 31/6615 Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7008 Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
• CPC Class Codes: A61K 31/7012 Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid gluconic acid A61K31/191; ascorbic acid A61K31/375
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/708 : having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/94 : Oxygen atom, e.g. piperidine N-oxide
• CPC Class Codes: C07D 473/16 : two nitrogen atoms
• CPC Class Codes: C07H 19/06 : Pyrimidine radicals
• CPC Class Codes: C07H 19/20 : with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07J 43/003 : not condensed
• CPC Class Codes: C07J 7/009 : by only one oxygen atom doubly bound

Abstract

The present invention provides a compound which is an inhibitor of sphingolipid biosynthesis for use in the treatment of a disease which has a secondary Niemann-Pick type C disease like cellular phenotype.

Claims

1. A method of treating a subject having a disease which has a secondary Niemann-Pick type C disease like cellular phenotype, wherein the disease is Smith-Lemli-Opitz Syndrome (SLOS), CHILD syndrome, XLD chondrodysplasia punctata type 2, Conradi-Hü

nnermann-Happle syndrome, or HEM dysplasia, the method comprising selecting the subject having the disease, and administering to the subject an effective amount of an inhibitor of sphingolipid biosynthesis wherein the inhibitor of sphingolipid biosynthesis is N-butyldeoxynojirimycin;

N-nonyldeoxynojirimycin;

N-butyldeoxygalactonojirimycin;

N-5-adamantane-1-yl-methoxypentyl-deoxynojirimycin;

alpha-homogalactonojirimycin;

nojirimycin;

deoxynojirimycin;

N7-oxadecyl-deoxynojirimycin;

deoxygalactonojirimycin;

N-butyl-deoxygalactonojirimycin;

N-nonyl-deoxygalactonojirimycin;

N-nonyl-6deoxygalactonojirimycin;

N7-oxanonyl-6deoxy-DGJ;

alpha-homoallonojirimycin;

or beta-1-C-butyl-deoxygalactonojirimycin.

2. The method of claim 1 wherein the inhibitor is an inhibitor of a glycosyltransferase or a sulfotransferase.

3. The method of claim 2 wherein the glycosyltransferase is a glucosyltransferase, sialyltransferase, galactosyltransferase, ceramide galactosyltransferase, fucosyltransferase, or N-acetylhexosaminetransferase.

4. The method of claim 1 wherein the inhibitor is an inhibitor of glucosylceramide synthase.

5. The method of claim 1 wherein the inhibitor is an inhibitor of ceramide biosynthesis.

6. The method of claim 1 wherein the inhibitor is an inhibitor of serine palmitoyltransferase or an inhibitor of dihydroceramide synthase.

7. The method of claim 1 wherein the inhibitor of sphingolipid biosynthesis is an inhibitor of ceramide degradation.

8. The method of claim 1 wherein the inhibitor of sphingolipid biosynthesis is an inhibitor of acidceramidase.

9. The method of claim 1 wherein the disease which has a secondary Niemann-Pick type C disease like cellular phenotype is a disease which incurs the accumulation of a class II amphiphile.

10. The method of claim 9 wherein the class II amphiphile is a precursor or analogue of cholesterol.

11. The method of claim 1 further comprising coadministering the compound with cholesterol and/or an inhibitor of de novo cholesterol biosynthesis, wherein the disease is Smith-Lemli-Opitz Syndrome (SLOS).

12. The method of claim 1, wherein the inhibitor of sphingolipid biosynthesis is N-butyldeoxynojirimycin, and the disease is Smith-Lemli-Opitz Syndrome (SLOS).

13. The method of claim 1, wherein the disease is Smith-Lemli-Opitz Syndrome (SLOS).