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Scaffold hopping towards potent and selective JAK3 inhibitors: Discovery of novel C-5 substituted pyrrolopyrazines
Affiliation:1. Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;2. Roche Palo Alto, 3401 Hillview Ave, Palo Alto, CA 94304, United States;1. Faculty of Health Sciences, University of Macau, Macau, China;2. School of Pharmacy, Xuzhou Medical College, Xuzhou, Jiangsu 221004, China;1. College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China;2. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;3. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;4. Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA;5. Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA;6. Vanderbilt Institute of Chemical Biology, Vanderbilt University/Vanderbilt University Medical Center, Nashville, TN 37232, USA;1. Syncom B.V., Kadijk 3, Groningen 9747 AT, The Netherlands;2. Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands;1. Department of Medical System Engineering, Gwangju Institute of Science and Technology (GIST), 123 Cheomdan-gwagiro, Buk-gu, Gwangju 61005, Republic of Korea;2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea;3. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea;4. National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea;5. College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea;6. School of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan;7. School of Life Science, Gwangju Institute of Science and Technology (GIST), Republic of Korea;1. Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji’nan, Shandong 250012, PR China;2. Georgia Research Alliance Eminent Scholar in Drug Discovery, Department of Chemistry, Georgia State University, United States
Abstract:The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.
Keywords:Kinase inhibitors  Janus kinase  JAK  Structure based drug design  Scaffold hopping  Intramolecular hydrogen bond
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