Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects |
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| Affiliation: | 1. Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada;2. Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA;1. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;2. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;1. Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA;2. Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA;1. Medicinal Chemistry and Natural Products Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, Merseyside, UK;2. Manchester Interdisciplinary Biocentre, 131 Princess Street, The University of Manchester, Manchester M1 7DN, UK;3. The Department of Chemistry, University of Reading, Reading RG6 6AD, UK;1. Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA;2. Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA;3. Pharmaron Beijing Co. Ltd, 6 Taihe Road, BDA, Beijing 100176, PR China;1. National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States;2. The Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK;3. Department of Medical Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK;4. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States;5. Department of Cellular and Molecular Medicine, Nordea Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen N, Denmark |
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| Abstract: | We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3 mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles. |
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| Keywords: | Stearoyl-CoA desaturase-1 SCD1 inhibitors Thiazolylpyridinone Liver selective Desaturation index |
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