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Discovery of triazines as selective PDE4B versus PDE4D inhibitors
Institution:1. Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA;2. Tetra Discovery Partners LLC, Grand Rapids, MI, USA;3. Beryllium, 7869 NE Day Rd. West, Bainbridge Island, WA 98110, USA;4. Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA;1. Dr. Reddys Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India;2. Department of Chemistry, Acharya Nagarjuna University, Guntur, Andhra Pradesh, India;3. Department of Chemistry, Krishna University, Krishna Dist., Andhra Pradesh, India;4. Doctoral Programme in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal;1. R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;2. Quality & Safety Management Division, Daiichi Sankyo Co., Ltd, 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo 103-8426, Japan;3. Corporate Strategy Division, Daiichi Sankyo Co., Ltd, 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo 103-8426, Japan;4. Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;1. Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China;2. College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China;3. Department of Pharmacy, Quanzhou Medical College, Quanzhou 362100, China;4. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;1. Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan;2. Department of Bioengineering, Tokyo Institute of Technology, Kanagawa 226-8501, Japan;3. Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan;4. Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan;1. Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ooty, Udhagamandalam 643001, Tamil Nadu, India;2. Constituent College of JSS University, Mysore, India
Abstract:In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive ‘closed’ conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors.
Keywords:PDE4 inhibitor  PDE4B  PDE4D  Crystallography  Triazine
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