COMPOSITIONS AND METHODS USEFUL FOR TREATING DISEASES CHARACTERIZED BY INSUFFICIENT PANTOTHENATE KINASE ACTIVITY
Methods and pharmaceutical compositions for use in treating diseases associated with insufficient activity of the pantothenate kinase enzyme (e.g., CASTOR diseases) are disclosed. The methods and compositions involve an effective amount of an active derivative of 4′-phosphopantetheine.
1 - 44 . (canceled)
45 . A method of treating a diseased subject having a Coenzyme A sequestration, toxicity or redistribution (CASTOR) disease, comprising administering to the diseased subject an effective amount of an active derivative of 4′-phosphopantetheine, wherein the active derivative of 4′-phosphopantetheine is a compound of Formula (I):
a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein:
Ra is H,
R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, COR 11 , C(O)OR 11 , C(O)NR 11 R 12 , C═NR 11 , CN, OR 11 , OC(O)R 11 , NR 11 R 12 , NR 11 C(O)R 12 , NO 2 , N═CR 11 R 12 , or halogen;
R 2 , R 3 , Rb, and Rc is each independently selected from the group consisting of H, methyl, ethyl, phenyl, acetoxymethyl (AM), pivaloyloxymethyl (POM),
or
R 2 and R 3 , or Rb and Rc, jointly form a structure selected from the group consisting of
wherein
R 4 is H or alkyl;
R 5 is H or alkyl;
R 6 is H, alkyl, or CH 2 (CO)OCH 3 ;
R 7 is H, alkyl, or halogen;
R 8 is H or alkyl;
R 9 is H or alkyl;
R 10 is H or-alkyl; and
R 11 and R 12 each is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, or halogen; and
wherein the diseased subject does not have a pantothenate kinase-associated neurodegeneration (PKAN) disease.
46 - 52 . (canceled)
53 . The method of claim 45 , wherein the CASTOR disease is associated with inhibition of one or more pantothenate kinases by one or more acyl Coenzyme A (acyl-CoA) species.
54 . The method of claim 45 , wherein the CASTOR disease is associated with accumulation of one or more acyl Coenzyme A (acyl-CoA) species in the diseased subject to amounts greater than that of a healthy subject not having the CASTOR disease.
55 . (canceled)
56 . The method of claim 45 , wherein the CASTOR disease is associated with impaired or inhibited degradation of the one or more acyl-CoA species in the diseased subject.
57 . The method of claim 45 , wherein the one or more acyl-CoA species are not acetyl Coenzyme A (acetyl-CoA).
58 . The method of claim 45 , wherein the CASTOR disease is associated with accumulation of one or more fatty acids in the diseased subject to amounts greater than that of a healthy subject not having the CASTOR disease.
59 . The method of claim 45 , wherein the CASTOR disease is associated with impaired or inhibited degradation of the one or more fatty acids in the diseased subject.
60 . The method of claim 45 , wherein the CASTOR disease is selected from the group consisting of medium-chain acyl-CoA dehydrogenase deficiency, biotinidase deficiency, isovaleric acidemia, very long-chain acyl-CoA dehydrogenase deficiency, long-chain L-3-OH acyl-CoA dehydrogenase deficiency, glutaric acidemia type I, 3-hydroxy-3-methylglutaric acidemia, trifunctional protein deficiency, multiple carboxylase deficiency, methylmalonic acidemia (methylmalonyl-CoA mutase deficiency), 3-methylcrotonyl-CoA carboxylase deficiency, methylmalonic acidemia (Cbl A,B), propionic acidemia, carnitine uptake defect, beta-ketothiolase deficiency, short-chain acyl-CoA dehydrogenase deficiency, glutaric acidemia type II, medium/short-chain L-3-OH acyl-CoA dehydrogenase deficiency, medium-chain ketoacyl-CoA thiolase deficiency, carnitine palmitoyltransferase II deficiency, methylmalonic acidemia (Cbl C,D), malonic acidemia, carnitine: acylcarnitine translocase deficiency, isobutyryl-CoA dehydrogenase deficiency, 2-methyl 3-hydroxybutyric aciduria, dienoyl-CoA reductase deficiency, 3-methylglutaconic aciduria, PLA2G6-associated neurodegeneration, glycine N-acyltransferase deficiency, 2-methylbutyryl-CoA-dehydrogenase-deficiency, mitochondrial acetoacetyl-CoA thiolase deficiency, dihydrolipoamide dehydrogenase deficiency/Branched chain alpha-ketoacid dehydrogenase (BCKDH) deficiency, 3-methylglutaconyl-CoA hydratase deficiency, 3-hydroxyisobutyrate dehydrogenase deficiency, 3-hydroxy-isobutyryl-CoA hydrolase deficiency, isobutyryl-CoA dehydrogenase deficiency, methylmalonate semialdehyde dehydrogenase deficiency, bile acid-CoA:amino acid N-acyltransferase deficiency, bile acid-CoA ligase deficiency, holocarboxylase synthetase deficiency, Succinate dehydrogenase deficiency, α-Ketoglutarate dehydrogenase deficiency, CoASY, glutaric acidemia type II/multiple acyl-CoA dehydrogenase deficiency, long chain 3-ketoacyl-CoA thiolase, D-3-hydroxyacyl-CoA dehydrogenase deficiency (part of DBD), acyl-CoA dehydrogenase 9 deficiency, Systemic primary carnitine deficiency, carnitine: acylcarnitine translocase deficiency I and II, acetyl-CoA carboxylase deficiency, Malonyl-CoA decarboxylase deficiency, Mitochondrial HMG-CoA synthase deficiency, succinyl-CoA:3-ketoacid CoA transferase deficiency, phytanoyl-CoA hydroxylase deficiency/Refsum disease, D-bifunctional protein deficiency (2-enoyl-CoA-hydratase and D-3-hydroxyacyl-CoA-dehydrogenase deficiency.), acyl-CoA oxidase deficiency, alpha-methylacyl-CoA racemase (AMACR) deficiency, sterol carrier protein x deficiency, 2,4-dienoyl-CoA reductase deficiency, Cytosolic acetoacetyl-CoA thiolase deficiency, Cytosolic HMG-CoA synthase deficiency, lecithin cholesterol acyltransferase deficiency, choline acetyl transferase deficiency, Congenital myasthenic syndrome, pyruvate dehydrogenase deficiency, phosphoenolpyruvate carboxykinase deficiency, pyruvate carboxylase deficiency, serine palmiotyl-CoA transferase deficiency/Hereditary sensory and autonomic neuropathy type I, and ethylmalonic encephalopathy.
61 - 62 . (canceled)
63 . The method of claim 60 , wherein the CASTOR disease is selected from the group consisting of medium chain acyl-CoA dehydrogenase deficiency, short chain acyl-CoA dehydrogenase deficiency, very long chain acyl-CoA dehydrogenase deficiency, and D-bifunctional protein deficiency.
64 - 67 . (canceled)
68 . The method of claim 60 , wherein the CASTOR disease is selected from the group consisting of Glutaric acidemia type 1, methylmalonic academia, propionyl-CoA carboxylase deficiency, propionic academia, 3-methylcrotonyl carboxylase deficiency, and isovaleryl-CoA dehydrogenase deficiency.
69 - 75 . (canceled)
76 . The method of claim 45 , wherein the compound of Formula (I) is a compound of Formula (Ia):
77 . The method of claim 45 , wherein R 1 is C 1 -C 10 alkyl.
78 . (canceled)
79 . The method of claim 77 , wherein R 1 is methyl.
80 . The method of claim 45 , wherein at least one of R 2 and R 3 is H.
81 - 82 . (canceled)
83 . The method of claim 45 , wherein the active derivative of 4′-phosphopantetheine is 4′-phosphopantetheine or a pharmaceutically acceptable salt thereof.
84 . The method of claim 45 , wherein the active derivative of 4′-phosphopantetheine is S-acyl-4′-phosphopantetheine or a pharmaceutically acceptable salt thereof.
85 . (canceled)
86 . The method of claim 45 , wherein the active derivative of 4′-phosphopantetheine is S-acetyl-4′-phosphopantetheine.
87 . (canceled)
88 . The method of claim 45 , wherein the active derivative of 4′-phosphopantetheine is a calcium salt of S-acetyl-4′-phosphopantetheine.
89 - 176 . (canceled)
177 . A pharmaceutical kit for use in the treatment of a diseased subject having a Coenzyme A sequestration, toxicity or redistribution (CASTOR) disease, comprising an effective amount of the active derivative of 4′-phosphopantetheine.
178 . A method of synthesizing the active derivative of 4′-phosphopantetheine, comprising the steps of:
i) chemically treating pantothenic acid with S-tritylcysteamine to form S-tritylpantetheine;
ii) chemically treating S-tritylpantetheine with dibenzylchlorophosphate to form S-trityl-4′-dibenzylphosphopantetheine; and
iii) chemically treating S-trityl-4′-dibenzylphosphopantetheine to form 4′-phosphopantetheine.
179 - 181 . (canceled)