Compositions and Methods for the Treatment of Metabolic and Related Disorders
The present invention relates to the compound for treatment and/or prevention of one or more metabolic disorders utilizes an A-B-C tripartite structure, wherein A, B, and C are identical or non-identical structures, for example, but not limited to, heterocyclic, phenyl or benzyl ring structures with or without substitutions and are described in detail herein. Also provided are methods for the treatment and/or prevention of one or more metabolic disorders, for example, obesity or diabetes, utilizing fatostatin A and/or a derivative and/or analog thereof and/or the A-B-C tripartite compounds.
1 . A compound having the chemical structure:
A-B-C
wherein A is a pyridine or a substituted pyridine, a piperidine or a substituted piperidine, a thiazole or a substituted thiazole, a benzimidazole or a substituted benzimidazole, a phenyl ring or a substituted phenyl ring;
B is a thioazole or a substituted thioazole, a piperazine or a substituted piperazine, a triazolopyridine or a substituted triazolopyridine, a phenyl ring or a substituted phenyl ring or wherein A and B together are a benzothiazole or a substituted benzothiazole; and
C is a phenyl ring or a substituted phenyl ring, a pyridine or a substituted pyridine, or a thioazole or a substituted thioazole.
2 . The compound of claim 1 , wherein the chemical structure is:
wherein R 1 is H, halogen, —OH, —O—C 1-3 alkoxy, —OC(O)R 3 or R 5 ;
R 2 is alkyl or R 8 OC(O) —;
R 3 is C 1 -C 3 alkyl or aryl, —OCH 2 —C(O)OR 4 ;
R 4 is H or C 1 -C 3 alkyl,
R 5 is H, C 1 -C 4 alkyl, alkylcyclopropane, benzyl, —NHC(O)C 1 -C 3 amide, —NHC(O)O—R 6 carbamate or —NH—SO 2 —R 7 sulfonamide;
R 6 is tert-butyl, fluorenylmethyl or —NH—SO 2 —R 7 sulfonamide;
R 7 is alkyl or aryl,
and
R 8 is C 3 -C 5 alkyl or aryl.
3 . The compound of claim 2 , wherein said halogen is bromine.
4 . The compound of claim 1 , wherein the chemical structure is:
wherein R 9 is H, halogen, —OH, —O—C 1 -C 3 alkoxy, —OC(O)R 11 ;
R 11 is C 1 -C 3 alkyl or aryl, —OCH 2 —C(O)OR 12 ;
R 12 is H or C 1 -C 3 alkyl, —NHR 13 ;
R 13 is H, C 1 -C 4 alkyl, alkylcyclopropane, benzyl, —NHC(O)C 1-3 amide, —NHC(O)O—R 14 carbamate;
R 14 is tert-butyl or fluorenylmethyl, —NH—SO 2 —R 15 sulfonamide;
R 15 is alkyl or aryl or —SO 2 —NH—R 16 sulfonamide;
R 16 is alkyl or aryl,
R 10 is nitrogen or methylene,
n is 0 or 1 and when n is 1, Z is —C═O; and
A is
wherein R 17 is H or C 1 -C 3 alkyl group.
5 . The compound of claim 1 , wherein the chemical structure is:
6 . The compound of claim 1 , wherein the chemical structure is:
7 . The compound of claim 1 , wherein the chemical structure is:
8 . The compound of claim 1 , wherein the chemical structure is:
9 . The compound of claim 1 , wherein the chemical structure is:
10 . The compound of claim 1 , wherein the chemical structure is:
11 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
12 . A method for treating a metabolic disorder in an individual, comprising the step of:
administering to the individual a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof.
13 . The method of claim 12 , wherein said metabolic disorder comprises obesity, hyperlipemia, diabetes or complications thereof, fatty liver, hypertension, prostate cancer or cardiovascular disease.
14 . The method of claim 12 , further comprising the step of:
providing an additional therapy to said individual.
15 . The method of claim 14 , wherein the additional therapy comprises dietary therapy, physical therapy, behavior therapy, surgery, drug therapy or a combination thereof.
16 . A method of inhibiting a member of a SREBP pathway in an individual, comprising the step of:
administering to the individual a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof.
17 . The method of claim 16 , wherein said member of a SREBP pathway is SREBP-1, SREBP-2, or both.
18 . A kit comprising:
the compound of claim 1 ; and
a container housing the compound.
19 . A compound that is:
1 tert-butyl 3-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate,
benzyl-3-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate,
3-(4-(4-bromophenyl)thiazol-2-yl)-1-propylpiperidine,
benzyl-4-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate,
benzyl-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)piperidine-1-carboxylate
benzyl-4-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)piperidine-1-carboxylate
N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide,
4-(3-(pyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N-tosylbenzenamine,
(4-(5-chloro-2-methylphenyl)piperazin-1-yl)(4-tosylamino)phenyl) methanone,
4-(4-((1-methyl-1H-benzo[d]imidazole-2-yl)methyl)piperazin-1-yl)-N-tosyl benzenamine,
3-chloro-4-methyl-N-(6-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)pyridin-3-yl) benzenesulfonamide
4-chloro-N-(4-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl) phenyl)benzenesulfonamide
(Z)-4-(3-cyano-3-(4-(2,4-dimethylphenyl)thiazol-2-yl)allyl)-N-(thiazol-2-yl)benzenesulfonamide
N-(3-(H-imidazo[1,2-a]pyridine-2-yl)phenyl)-4-methyl-2-phenylthiazole-5-carboxamide,
N-(3-(benzo[d]thiazol-2-yl)phenyl)isonicotinamide,
3-(4-chlorophenyl)-4,5-dihydro-1-phenyl-5-(2-phenylthiazol-4-yl)-1H-pyrazole,
N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-m-tolylmethylsulfonamido) acetamide; or
N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-p-tolylmethylsulfonamido) acetamide.