Discovery of novel inhibitors of phosphodiesterase 4 with 1-phenyl-3,4-dihydroisoquinoline scaffold: Structure-based drug design and fragment identification |
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| Institution: | 1. College of Materials and Energy, State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou 510642, China;2. Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China;3. Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China;4. Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632, China;1. College of life and Environmental Sciences, Hunan University of Arts and Science, No. 3150 Dongting Avenue, Changde, Hunan, China;2. Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, 348 West XianJiahu Road, Changsha, Hunan, China;1. College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China;2. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China;3. Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632, China;4. State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China;1. Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India;2. Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal 576 104, Karnataka, India;1. DBT-Bioinformatics Infrastructure Facility, Centre for Biotechnology and Bioinformatics, School of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India;2. Centre for Biotechnology and Bioinformatics, School of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India;3. Department of Chemistry, School of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India;1. Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India;2. Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education, Madhav Nagar, Manipal 576 104, Karnataka, India;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 |
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| Abstract: | Currently, it is in urgent need to develop novel selective PDE4 inhibitors with novel structural scaffolds to overcome the adverse effects and improve the efficacy. Novel 1-phenyl-3,4-dihydroisoquinoline amide derivatives were developed as potential PDE4 inhibitors based on the structure-based drug design and fragment identification strategy. A SARs analysis was performed in substituents attached in the C-3 side chain phenyl ring, indicating that the attachment of methoxy group or halogen atom substitution at the ortho-position of the phenyl ring was helpful to enhance both inhibitory activity toward PDE4B and selectivity. Compound 15 with excellent selectivity, exhibited the most potent inhibition in vitro and in vivo, which is a promising lead for development of a new class of selective PDE4 inhibitors. |
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| Keywords: | Selective PDE4B inhibitors 1-Phenyl-3 4-dihydroisoquinoline Synthesis Structure-activity relationships |
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