SPT5 inhibitors and uses thereof
Provided are compounds which are Spt5 inhibitors and which are for use in the treatment diseases and disorders in which inhibiting one or more activities of Spt5 is beneficial, such as, for example, Trinucleotide repeat disorders, obesity, inflammatory diseases, infectious diseases and cancer. The compounds are represented by Formulae I-VII, as defined in the specification.
1 . A method of treating a nucleotide repeat disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by Formula Ia:
wherein:
n and m are each independently an integer of from 0 to 4;
R 1 and R 2 are each independently a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, thiol, alkoxy, thioalkoxy, aryloxy, thioaryloxy, halo, alkyl, amine, amide, nitro, carboxylate and thiocarboxylate;
B is a heteroaryl or a heteroalicyclic; and
L is a linking moiety, comprising from 2 to 12 atoms in length, and comprising a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain, interrupted by at least one S,
thereby treating a nucleotide repeat disorder in the subject;
said nucleotide repeat disorder is a trinucleotide repeat disorder selected from Huntington disease, fragile X syndrome, Fragile XE mental retardation, Fragile X-associated tremor/ataxia syndrome, mitotic dystrophy type 1 (DM1), spino-bulbar muscular atrophy (SBMA), Jacobsen syndrome, Spinocerebellar ataxia (SCA) type 1, SCA 2, SCA3 (also known as Machado-Joseph disease), SCA6, SCAT, SCA 7, SCA 8 SCA 12, SCA 17, dentatorubral pallidoluysian atrophy, Friedreich ataxia, Huntington disease-like 2, oculopharyngeal muscular dystrophy, multiple epiphyseal dysplasia, cleidocranial dysplasia, and synpolydactyly.
2 . The method of claim 1 , wherein L is a substituted, saturated hydrocarbon interrupted by said at least one S, and optionally further interrupted by O.
3 . The method of claim 1 , wherein the compound inhibits binding of Spt5 to Pol II or changes the conformation of a Spt5-Pol II complex.
4 . A method of treating a nucleotide repeat disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group of compounds presented in Tables 6, 7, 8 and 9-, thereby treating the nucleotide repeat disorder in the subject;
said nucleotide repeat disorder is a trinucleotide repeat disorder selected from Huntington disease, fragile X syndrome, Fragile XE mental retardation, Fragile X-associated tremor/ataxia syndrome, mitotic dystrophy type 1 (DM1), spino-bulbar muscular atrophy (SBMA), Jacobsen syndrome, Spinocerebellar ataxia (SCA) type 1, SCA 2, SCA3 (also known as Machado-Joseph disease), SCA6, SCAT, SCA 7, SCA 8 SCA 12, SCA 17, dentatorubral pallidoluysian atrophy, Friedreich ataxia, Huntington disease-like 2, oculopharyngeal muscular dystrophy, multiple epiphyseal dysplasia, cleidocranial dysplasia, and synpolydactyly.
5 . The method of claim 4 , wherein said compound inhibits binding of Spt5 to Pol II or changes the conformation of a Spt5-Pol II complex.
6 . The method of claim 1 , wherein B is an oxazole or a thiazole.
7 . The method of claim 1 , wherein n is 1 and R 1 is an electron-donating group selected from amine, thioalkoxy, and alkoxy.
8 . The method of claim 1 , wherein said compound is
9 . The method of claim 1 , wherein said trinucleotide repeat disorder is Huntington's disease.
10 . The method of claim 4 , wherein said trinucleotide repeat disorder is Huntington's disease.