US 2015/0307487 A1Published application

SMALL MOLECULES TARGETING REPEAT r(CGG) SEQUENCES

AssigneeThe Scripps Research Institute

InventorsMatthew D. Disney, Biao Liu, Jessica L. Childs-Disney, Wang-Yong Yang

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Abstract

The invention provides a series of bioactive small molecules that target expanded r(CGG) repeats, termed r(CGG)exp, that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium, binds the 5′CG/3′GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Specifically, dimeric compounds incorporating two 9-hydroxyellipticine analog structures can even more potently bind the 5′CGG/3′GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Structure-activity relationships (SAR) studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG) repeats, such as r(CGG)exp. Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)exp-protein aggregates.

Claims29

Dependent claims

A compound of formula (I)

wherein
R1 is H, (C1-C6)alkyl, or (C1-C6)alkanoyl;
R2 is H, (C1-C6)alkyl, or (C1-C6)alkanoyl;
R3 and R4 are independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxyalkyl (C1-C6)haloalkoxyalkyl, or (C6-C10)aryl;
R5 is (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, aryl(C1-C6)alkyl, heterocyclyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or (R6)2N—(C1-C6)alkyl, wherein R6 is H or (C1-C6)alkyl;
wherein any alkyl, alkanoyl, alkoxy, aryl, heterocyclyl, or heteroaryl group can be substituted with 0-3 J groups, wherein J is any of halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, hydroxy(C1-C6)alkyl, alkoxy(C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, cyano, nitro, azido, R2N, R2NC(O), R2NC(O)O, R2NC(O)NR, (C1-C6)alkenyl, (C1-C6)alkynyl, (C6-C, 10)aryl, (C6-C10)aryloxy, (C6-C10)aroyl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy, (C6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryloxy(C, 1-C6)alkoxy, (3- to 9-membered)heterocyclyl, (3- to 9-membered)heterocyclyl(C1-C6)alkyl, (3- to 9-membered)heterocyclyl(C1-C6)alkoxy, (5- to 10-membered)heteroaryl, (5- to 10-membered)heteroaryl(C1-C6)alkyl, (5- to 10-membered)heteroaryl(C1-C6)alkoxy, or (5- to 10-membered)heteroaroyl;
R is independently at each occurrence H, (C1-C6)alkyl, or (C6-C10)aryl, wherein any alkyl or aryl group is substituted with 0-3 J;
or,
a dimeric r(CGG) binding compound of formula (II)
wherein R1, R2, R3, and R4 are as defined for the monomeric compound of formula (I), and wherein L is a linker comprising a polypeptide backbone bonded by two respective nitrogen atoms thereof to a nitrogen atom of a respective 1,2,3-triazole group via a respective (C1-C6)alkylene group optionally further comprising a glycyl residue, each respective triazole group being bonded via a (C1-C6)alkylene group to the respective pyridinium nitrogen atom of each ellipticine scaffold;
or a pharmaceutically acceptable salt thereof;
provided the compound of formula (I) is not any of
or a pharmaceutically acceptable salt thereof.

10 more elements

A method of inhibiting a messenger RNA molecule with an repeat r(CGG) sequence from binding to a protein with a binding affinity for a RNA hairpin loop comprising a non-Watson-Crick G-G nucleotide pair, comprising contacting the messenger RNA molecule having the repeat r(CGG) sequence and an effective amount or concentration of a compound of formula (I)

wherein
R1 is H, (C1-C6)alkyl, or (C1-C6)alkanoyl;
R2 is H, (C1-C6)alkyl, or (C1-C6)alkanoyl;
R3 and R4 are independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxyalkyl (C1-C6)haloalkoxyalkyl, or (C6-C10)aryl;
R5 is (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, aryl(C1-C6)alkyl, heterocyclyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or (R6)2N—(C1-C6)alkyl, wherein R6 is H or (C1-C6)alkyl;
wherein any alkyl, alkanoyl, alkoxy, aryl, heterocyclyl, or heteroaryl group can be substituted with 0-3 J groups, wherein J is any of halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, hydroxy(C1-C6)alkyl, alkoxy(C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, cyano, nitro, azido, R2N, R2NC(O), R2NC(O)O, R2NC(O)NR, (C1-C6)alkenyl, (C1-C6)alkynyl, (C6-C, 10)aryl, (C6-C10)aryloxy, (C6-C10)aroyl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy, (C6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryloxy(C, 1-C6)alkoxy, (3- to 9-membered)heterocyclyl, (3- to 9-membered)heterocyclyl(C1-C6)alkyl, (3- to 9-membered)heterocyclyl(C1-C6)alkoxy, (5- to 10-membered)heteroaryl, (5- to 10-membered)heteroaryl(C1-C6)alkyl, (5- to 10-membered)heteroaryl(C1-C6)alkoxy, or (5- to 10-membered)heteroaroyl;
R is independently at each occurrence H, (C1-C6)alkyl, or (C6-C10)aryl, wherein any alkyl or aryl group is substituted with 0-3 J;
or,
an effective amount or concentration of a dimeric r(CGG) binding compound of formula (II)
wherein R1, R2, R3, and R4 are as defined for the monomeric compound of formula (I), and wherein L is a linker comprising a polypeptide backbone bonded by two respective nitrogen atoms thereof to a nitrogen atom of a respective 1,2,3-triazole group via a respective (C1-C6)alkylene group optionally further comprising a glycyl residue, each respective triazole group being bonded via a (C1-C6)alkylene group to the respective pyridinium nitrogen atom of each ellipticine scaffold;
or a pharmaceutically acceptable salt thereof;
or a pharmaceutically acceptable salt thereof.

9 more elements

A method of treatment of Fragile X-associated Tremor Ataxia Syndrome, comprising administering to a patient afflicted therewith a therapeutically effective dose of a compound of formula (I)

wherein
R1 is H, (C1-C6)alkyl, or (C1-C6)alkanoyl;
R2 is H, (C1-C6)alkyl, or (C1-C6)alkanoyl;
R3 and R4 are independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxyalkyl (C1-C6)haloalkoxyalkyl, or (C6-C10)aryl;
R5 is (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, aryl(C1-C6)alkyl, heterocyclyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or (R6)2N—(C1-C6)alkyl, wherein R6 is H or (C1-C6)alkyl;
wherein any alkyl, alkanoyl, alkoxy, aryl, heterocyclyl, or heteroaryl group can be substituted with 0-3 J groups, wherein J is any of halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, hydroxy(C1-C6)alkyl, alkoxy(C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, cyano, nitro, azido, R2N, R2NC(O), R2NC(O)O, R2NC(O)NR, (C1-C6)alkenyl, (C1-C6)alkynyl, (C6-C, 10)aryl, (C6-C10)aryloxy, (C6-C10)aroyl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy, (C6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryloxy(C, 1-C6)alkoxy, (3- to 9-membered)heterocyclyl, (3- to 9-membered)heterocyclyl(C1-C6)alkyl, (3- to 9-membered)heterocyclyl(C1-C6)alkoxy, (5- to 10-membered)heteroaryl, (5- to 10-membered)heteroaryl(C1-C6)alkyl, (5- to 10-membered)heteroaryl(C1-C6)alkoxy, or (5- to 10-membered)heteroaroyl;
R is independently at each occurrence H, (C1-C6)alkyl, or (C6-C10)aryl, wherein any alkyl or aryl group is substituted with 0-3 J;
or,
an effective amount or concentration of a dimeric r(CGG) binding compound of formula (II)
wherein R1, R2, R3, and R4 are as defined for the monomeric compound of formula (I), and wherein L is a linker comprising a polypeptide backbone bonded by two respective nitrogen atoms thereof to a nitrogen atom of a respective 1,2,3-triazole group via a respective (C1-C6)alkylene group optionally further comprising a glycyl residue, each respective triazole group being bonded via a (C1-C6)alkylene group to the respective pyridinium nitrogen atom of each ellipticine scaffold;
or a pharmaceutically acceptable salt thereof;
or a pharmaceutically acceptable salt thereof.

9 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/424,761Filed 30 Aug 2013
Priority: 30 Aug 2012
Published: 29 Oct 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/475
Quinolines; Isoquinolines: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
A61K 47/65
The modifying agent being a protein, peptide or polyamino acid: peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
C07D 519/00
Heterocyclic compounds containing more than one system of two or more relevant