Small molecule analogs of the nemo binding peptide
The invention is directed to a method of inhibiting, within a living cell, the interaction between NF-κB essential modulator (“NEMO”) with IκB kinase-β (IKK-β) at the NEMO binding domain (NBD), comprising exposing the cell to an effective amount or concentration of a compound of the invention, a NEMO-binding domain analog (NBDA). The invention is further directed to a method of treating a condition in a patient, wherein inhibiting the interaction between NF-κB essential modulator (“NEMO”) with IκB kinase-β (IKK-β) at the NEMO binding domain (NBD) is medically indicated, comprising administering to the patient an effective dose of a compound of the invention. Conditions that can be treated by a method of the invention includes muscular dystrophy, asthma, inflammatory bowel disease, multiple sclerosis, Parkinson's Disease, arthritis, diabetes, graft versus host disease, accelerated aging, heart ischemia, cancer, UV-induced skin damage, or an age-related pathology.
1. A method of inhibiting, within a living cell, the interaction of NF-κB essential modulator (NEMO) with IκB kinase-β (IKK-β) at the NEMO binding domain (NBD), comprising exposing the cell to an effective amount or concentration of a compound of formula (IA)
wherein
the ring bonded to Y comprises 0 or 1 nitrogen atom;
R is H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, or (C 2 -C 6 )acyl;
each R 1 is independently selected from halo, alkyl, and haloalkyl; m1=0, 1, 2, or 3;
each R 2 is independently selected from halo, alkyl, and haloalkyl; m2=0, 1, 2, or 3;
L is a bond, or is C(═O);
X is (CH 2 ) n , O, O(CH 2 ) n , (CH 2 ) n O, NR, (CH 2 ) n NR, or NR(CH 2 ) n ;
Y is C(═O), C(═O)(CH 2 ) n , NR, NR(CH 2 ) n , C(═O)NR, or C(═O)NR(CH 2 ) n ;
n=1, 2, or 3;
or a pharmaceutically acceptable salt or a hydrate thereof.
2. The method of claim 1 , wherein the compound of formula ( 1 A) is not any of
3. The method of claim 1 , wherein L is C═O.
4. A method of inhibiting, within a living cell, the interaction of NF-κB essential modulator (NEMO) with IκB kinase-β (IKK-β) at the NEMO binding domain (NBD), comprising exposing the cell to an effective amount or concentration of a compound selected from the following table: