- Improvement of pharmacological properties of irreversible thyroid receptor coactivator binding inhibitors
-
We have previously reported the discovery and preliminary structure activity relationships of a series of β-aminoketones that disrupt the binding of coactivators to TR. However, the most active compounds had moderate inhibitory potency and relatively high cytotoxicity, resulting in narrow therapeutic index. Additionally, preliminary evaluation of in vivo toxicology revealed a significant dose related cardiotoxicity. Here we describe the improvement of pharmacological properties of thyroid hormone receptor coactivator binding inhibitors. A comprehensive survey of the effects of substitutents in key areas of the molecule was carried out based on mechanistic insight from the earlier report. This study revealed that both electron withdrawing and hydrophobic substituents on the aromatic ring led to higher potency. On the other hand, moving from an alkyl to a sulfonyl alkyl side chain led to reduced cytotoxicity. Finally, utilization of amine moieties having low pKa's resulted in lowered ion channel activity without any loss of pharmacological activity.
- Jong, Yeon Hwang,Arnold, Leggy A.,Zhu, Fangyi,Kosinski, Aaron,Mangano, Thomas J.,Setola, Vincent,Roth, Bryan L.,Guy, R. Kiplin
-
supporting information; experimental part
p. 3892 - 3901
(2010/02/17)
-
- 5-Aryl-imidazolin-2-ones as a scaffold for potent antioxidant and memory-improving activity
-
A series of 5-phenyl-substituted-N-alkyl-imidazolin-2-ones with potent radical-scavenging activity and lipid peroxidation inhibitory activity was synthesized. Many of the compounds showed memory-improving effect in animal models independent of the inhibitory activity on lipid peroxidation.
- Watanabe, Kazutoshi,Morinaka, Yasuhiro,Hayashi, Yoshio,Shinoda, Masaki,Nishi, Hiroyoshi,Fukushima, Nobuko,Watanabe, Toshiaki,Ishibashi, Akira,Yuki, Satoshi,Tanaka, Masahiko
-
p. 1478 - 1483
(2008/09/18)
-
- Catalytic Friedel-Crafts acylation of alkoxybenzenes mediated by aluminum hydrogensulfate in solution and solvent-free conditions
-
Friedel-Crafts acylation of alkoxybenzenes was achieved efficiently by a reaction with aliphatic acid anhydrides in the presence of catalytic amounts of aluminum hydrogensulfate, Al(HSO4)3, in nitromethane and under solvent-free conditions. Alkylbenzenes and aryl halides, as well as aromatic anhydrides, remained intact under these conditions.
- Salehi, Peyman,Khodaei, Mohammad Mehdi,Zolfigol, Mohammad Ali,Sirouszadeh, Sara
-
p. 1863 - 1864
(2007/10/03)
-
- Catalytic Friedel-Crafts acylation of alkoxy benzenes by ferric hydrogensulfate
-
Friedel-Crafts acylation of alkoxy benzenes is achieved efficiently by reaction with aliphatic acid anhydrides in the presence of catalytic amounts of ferric hydrogensulfate, Fe(HSO4)3, in nitromethane. Alkyl benzenes and aryl halides, as well as aromatic anhydrides, remain intact under these conditions.
- Salehi, Peyman,Khodaei, Mohammad Mahdi,Zolfigol, Mohammad Ali,Zeinoldini, Shahpour
-
p. 1367 - 1373
(2007/10/03)
-