Discovery of novel non-carboxylic acid 5-amino-4-cyanopyrazole derivatives as potent and highly selective LPA1R antagonists |
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| Institution: | 1. Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA;2. Inflammation Discovery and Translational Area, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA;3. Discovery Technology, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA;1. Faculty of Chemistry, University of Wroclaw, Joliot-Curie 14, 50-383 Wroclaw, Poland;2. Universidade do Minho, Centro de Fisica, Campus de Gualtar, 4710-057 Braga, Portugal;3. Universidade d Minho, Centro de Fisica, Campus de Gualtar, 4710-057 Braga, Portugal;4. Department of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland;1. Institut für Neurobiochemie, Medizinische Fakultät, Otto-von-Guericke Universität, Leipziger Str. 44, 39120 Magdeburg, Germany;2. Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel;1. Kazan (Volga Region) State University, Kremlevskaya Str. 18, 420008 Kazan, Russian Federation;2. A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Centre of RAS, Arbuzov Str. 8, 420088 Kazan, Russian Federation;3. Kazan State Medical Academy, Mushtary Str. 11, 420010 Kazan, Russian Federation;1. Johns Hopkins University, Department of Chemistry, Baltimore, CA 21218, United States;2. Kongju National University, Department of Chemistry, 182, Shinkwan-dong, Kongju, Chungnam 314-701, Republic of Korea;1. Department of Electrical and Computer Engineering, Carnegie Mellon University, Silicon Valley, CA, USA;2. Department of Chemistry, Princeton University, Princeton, NJ, USA |
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| Abstract: | High throughput screening (HTS) of our chemical library identified 3-alkylamino-2-aryl-5H-imidazo1,2,b]pyrazol-7-carbonitrile 1 as a potent antagonist of the LPA1 receptor (LPA1R). Further evaluation of this class of compounds indicated that LPA1R antagonist activity originated from the degradation of the parent molecule in DMSO during the assay conditions. Here, we describe the isolation and characterization of the degradation products and their LPA1R antagonist activity. We further profiled these novel non-carboxylic acid LPA1R antagonists and demonstrated their inhibition of LPA-induced proliferation and contraction of normal human lung fibroblasts (NHLF). |
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| Keywords: | Novel LPA1 antagonists |
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