ABSTRACT
We report the design, synthesis, and biological activity of a series of compounds that exhibit potent mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) inhibition. Structural transformation of the substructures of a starting compound gave amidomethyl derivatives and sulfonylguanidine derivatives that exhibited potent inhibition of MALT1. Compound 37 had good oral bioavailability and showed anti-psoriatic activity in an imiquimod-induced psoriasis mouse model after oral administration.
Subject(s)
Lymphoma, B-Cell, Marginal Zone , Psoriasis , Mice , Animals , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein , Psoriasis/chemically induced , Psoriasis/drug therapyABSTRACT
The mitochondrial outer membrane protein mitoNEET is a binding protein of the insulin sensitizer pioglitazone (5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione) and is considered a novel target for the treatment of type II diabetes. Several small-molecule compounds have been identified as mitoNEET ligands using structure-based design or virtual docking studies. However, there are no reports about their therapeutic potential in animal models. Recently, we synthesized a novel small molecule, TT01001 [ethyl-4-(3-(3,5-dichlorophenyl)thioureido)piperidine-1-carboxylate], designed on the basis of pioglitazone structure. In this study, we assessed the pharmacological properties of TT01001 in both in vitro and in vivo studies. We found that TT01001 bound to mitoNEET without peroxisome proliferator-activated receptor-γ activation effect. In type II diabetes model db/db mice, TT01001 improved hyperglycemia, hyperlipidemia, and glucose intolerance, and its efficacy was equivalent to that of pioglitazone, without the pioglitazone-associated weight gain. Mitochondrial complex II + III activity of the skeletal muscle was significantly increased in db/db mice. We found that TT01001 significantly suppressed the elevated activity of the complex II + III. These results suggest that TT01001 improved type II diabetes without causing weight gain and ameliorated mitochondrial function of db/db mice. This is the first study that demonstrates the effects of a mitoNEET ligand on glucose metabolism and mitochondrial function in an animal disease model. These findings support targeting mitoNEET as a potential therapeutic approach for the treatment of type II diabetes.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Iron-Binding Proteins/metabolism , Membrane Proteins/metabolism , Mitochondria, Muscle/drug effects , Mitochondrial Proteins/metabolism , Piperidines/therapeutic use , Thiourea/analogs & derivatives , Animals , Blood Glucose/analysis , DNA, Mitochondrial/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Escherichia coli/genetics , Fluorescence Resonance Energy Transfer , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacology , Ligands , Male , Mice, Inbred Strains , Mitochondria, Muscle/enzymology , Mitochondria, Muscle/physiology , Mitochondrial Proteins/genetics , PPAR gamma/metabolism , Piperidines/administration & dosage , Piperidines/pharmacology , Surface Plasmon Resonance , Thiourea/administration & dosage , Thiourea/pharmacology , Thiourea/therapeutic useABSTRACT
We aimed to create a novel and potent α(1L)-adrenoceptor agonist because such agonists are possible drug candidates for stress urinary incontinence. We used ligand-based drug design and evaluated the α(1L)-adrenoceptor agonist activity of the designed compounds. Among them, tetrahydroquinoline derivative 50 showed the most potent activity (ratio of noradrenaline half maximal effective concentration, 0.0028) and effectively induced contraction of rat bladder neck.
Subject(s)
Adrenergic alpha-1 Receptor Agonists/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Drug Discovery , Adrenergic alpha-1 Receptor Agonists/chemistry , Adrenergic alpha-1 Receptor Agonists/pharmacology , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Molecular Structure , Quinolines/chemistry , Quinolines/pharmacology , Rats , Urinary Bladder/drug effectsABSTRACT
[reaction: see text] The radical trifluoromethylation of ketone silyl enol ethers gave alpha-CF(3) ketones in good yields with wide scope of the ketonic substrates including acyclic ketones and cyclopentanone. The use of dialkylzinc to activate the silyl enol ethers is the key to the efficient radical trifluoromethylation.