Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists |
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| Institution: | 1. Vertex Pharmaceuticals Inc., Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States;2. Vertex Pharmaceuticals Inc., Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States;3. Vertex Pharmaceuticals Inc., Department of Drug Metabolism and Pharmacokinetics, 11010 Torreyana Road, San Diego, CA 92121, United States;4. Vertex Pharmaceuticals Inc., Department of Structural Biology, 130 Waverly Street, Cambridge, MA 02139, United States;5. Aspyrian Therapeutics Inc., 11189 Sorrento Valley Rd, San Diego CA 92121, United States;1. Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA;2. TCG Lifesciences Limited, Salt Lake Electronic Complex, Block BN, Plot 7, Sector V, Kolkata 700 091, India;3. Metabolic and Vascular Diseases, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA;1. CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;2. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;3. Topharman Shanghai Co., Ltd, 388 Jialilue Road, Shanghai 201203, China;1. Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumchi 830011, China;2. University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China;3. CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;4. Topharman Shanghai Co., Ltd., 1088 Chuansha Road, Shanghai 201209, China |
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| Abstract: | Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (Ki = 30 pM, IC50 = 1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties. |
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| Keywords: | Migraine CGRP antagonists Thiazolidinone |
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