ABSTRACT
As a result of a hit-to-lead program using a technique of solution-phase parallel synthesis, a highly potent (2,4-dimethoxyphenyl)-[6-(3-fluorophenyl)-4-hydroxy-3-methylbenzofuran-2-yl]methanone (15b) was synthesized as an optimized derivative of 4-hydroxy-3-methyl-6-phenylbenzofuran-2-carboxylic acid ethyl ester (1), which was discovered as a screening hit from small-molecule libraries and exhibited selective cytotoxicity against a tumorigenic cell line.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzofurans/chemical synthesis , Carboxylic Acids/chemical synthesis , Cell Line, Tumor , Combinatorial Chemistry Techniques/methods , HumansABSTRACT
Based on the structure of 4-hydroxy-3-methyl-6-phenylbenzofuran-2-carboxylic acid ethyl ester (1), which exhibits selective cytotoxicity against a tumorigenic cell line, (2,4-dimethoxyphenyl)-(4-hydroxy-3-methyl-6-phenylbenzofuran-2-yl)-methanone (18m) was designed and synthesized as a biologically stable derivative containing no ester group. Although the potency of 18m was almost the same as our initial hit compound 1, 18m is expected to last longer in the human body as an anticancer agent.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzofurans/chemical synthesis , Carboxylic Acids/chemical synthesis , Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Carboxylic Acids/pharmacology , Cell Line, Tumor , Esters , HumansABSTRACT
A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Carbamates/pharmacology , Carbamates/therapeutic use , Carrier Proteins/antagonists & inhibitors , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Fumarates/pharmacology , Fumarates/therapeutic use , Membrane Glycoproteins/antagonists & inhibitors , Membrane Transport Proteins , Nerve Tissue Proteins/antagonists & inhibitors , Acetylcholinesterase/metabolism , Administration, Oral , Aging/drug effects , Aging/physiology , Alzheimer Disease/metabolism , Animals , Carbamates/chemistry , Carrier Proteins/physiology , Cholinesterase Inhibitors/chemistry , Fumarates/chemistry , Hippocampus/drug effects , Hippocampus/enzymology , Hippocampus/metabolism , Male , Maze Learning/drug effects , Maze Learning/physiology , Membrane Glycoproteins/physiology , Memory/drug effects , Memory/physiology , Mice , Microdialysis , Motor Activity/drug effects , Motor Activity/physiology , Nerve Tissue Proteins/physiology , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Rats, Wistar , Serotonin Plasma Membrane Transport ProteinsABSTRACT
Alzheimer's disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a previous paper, we found a potential dual inhibitor, 1, of AChE (IC50=101 nM) and SERT (IC50=42 nM), but its AChE inhibition activity was less than donepezil (IC50=10 nM). Here, we report the conformationally restricted (R)-18a considerably enhanced inhibitory activity against AChE (IC50=14 nM) and SERT (IC50=6 nM).
Subject(s)
Carrier Proteins/antagonists & inhibitors , Cholinesterase Inhibitors/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Membrane Glycoproteins/antagonists & inhibitors , Membrane Transport Proteins , Nerve Tissue Proteins , Alzheimer Disease/drug therapy , Animals , Cholinesterase Inhibitors/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mice , Molecular Conformation , Rats , Serotonin Plasma Membrane Transport Proteins , Structure-Activity RelationshipABSTRACT
We have designed and synthesized a dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT) as a novel class of treatment drugs for Alzheimer's disease on the basis of a hypothetical model of the AChE active site. Dual inhibitions of AChE and SERT would bring about greater therapeutic effects than AChE inhibition alone and avoid adverse peripheral effects caused by excessive AChE inhibition. Compound (S)-6j exhibited potent inhibitory activities against AChE (IC(50)=101 nM) and SERT (IC(50)=42 nM). Furthermore, (S)-6j showed inhibitory activities of both AChE and SERT in mice brain following oral administration.
Subject(s)
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Carrier Proteins/antagonists & inhibitors , Cholinesterase Inhibitors/chemical synthesis , Drug Design , Membrane Glycoproteins/antagonists & inhibitors , Membrane Transport Proteins , Nerve Tissue Proteins , Alzheimer Disease/metabolism , Animals , Carrier Proteins/metabolism , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Dose-Response Relationship, Drug , Membrane Glycoproteins/metabolism , Mice , Rats , Serotonin Plasma Membrane Transport Proteins , Structure-Activity RelationshipABSTRACT
Highly efficient acetylcholinesterase (AChE) and serotonin transporter (SERT) dual inhibitors, (S)-4 and (R)-13 were designed and synthesized on the basis of the hypothetical model of AChE active site. Both compounds showed potent inhibitory activities against AChE and SERT. [structure: see text]
