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Discovery of S-adenosyl-l-homocysteine hydrolase inhibitors based on non-adenosine analogs
Affiliation:1. Medicinal Chemistry Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan;2. Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan;1. Department of Ophthalmology, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan;2. Department of Neurobiology, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan;3. Department of Pharmacology, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan;4. Department of Ophthalmology, Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan;1. Department of Environmental Health Sciences, Kochi University, Kochi 783-8505, Japan;2. Department of Immunology, Research Institute for Tropical Medicine, Muntinlupa 1781, Philippines;3. Laboratory of Biochemistry, Faculty of Science, Kochi University, Kochi 780-8520, Japan;1. University of Turin, Department of Mathematics “Giuseppe Peano”, via Carlo Alberto 10, I-10123 Torino, Italy;2. Universidad de Granada, Departamento de Álgebra Facultad de Educación, Economía y Tecnología de Ceuta, Cortadura del Valle, s/n, E-51001 Ceuta, Spain;1. Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan;2. South Ehime Fisheries Research Center, 1289-1 Funakoshi, Ainan, Ehime 798-4292, Japan;3. Integrated Center for Sciences, Tarumi Station, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan;1. Nagoya University Graduate School of Medicine, Aichi, Japan;2. Chukyo Hospital, Aichi, Japan;3. Komaki City Hospital, Aichi, Japan
Abstract:High throughput screening using Automated Ligand Identification System (ALIS) resulted in the discovery of a new series of S-adenosyl-l-homocysteine hydrolase inhibitors based on non-adenosine analogs. The optimization campaign led to very potent and competitive compound 39 with a Ki value of 1.5 nM. Compound 39 could be a promising lead compound for research to reduce elevated homocysteine levels.
Keywords:Homocysteine  Competitive
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