Potent,non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes |
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| Affiliation: | 1. Department of Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. WuXi AppTec Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China;1. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China;2. Department of Respiratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;1. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China;2. Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;1. College of Pharmacy, College of Laboratory Medicine, Dalian Medical University, Dalian 116044, PR China;2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China;3. Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China;2. Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, PR China;1. Biogen Inc., 225 Binney Street, Cambridge, MA 02142, United States;2. Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, South San Francisco, CA 94080, United States |
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| Abstract: | Bruton’s tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model. |
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| Keywords: | Bruton’s Tyrosine Kinase Structure based drug design Kinase selectivity Rat CIA model X-ray crystal structure |
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