(R)-3-Amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: Design,synthesis, biological evaluation,and molecular modeling |
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| Affiliation: | 1. Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA;2. Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China;3. Platform Technology and Science, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, PR China;4. Platform Technology and Science, GlaxoSmithKline, 5 Moore Drive, RTP, NC 27709, USA;5. Harvard Stem Cell Institute, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA;6. Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK;1. Department of Chemistry, National Taiwan University, Taipei 106, Taiwan;2. The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan;3. National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan;1. Department of Earth Resources Engineering, Kyushu University, Fukuoka 819-0395, Japan;2. Department of Advanced Device Materials, Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga 816-8180, Japan;1. Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Karl-Franzens-University, Schubertstrasse 1, Graz A-8010, Austria;2. Swiss Tropical and Public Health Institute, Socinstrasse 57, Basel CH-4002, Switzerland;3. University of Basel, Petersplatz 1, Basel CH-4003, Switzerland;4. Institute for Chemistry and Technology of Materials (ICTM), Graz University of Technology, Stremayrgasse 9, Graz A-8010, Austria;5. Institute of Pharmaceutical Sciences, Pharmacognosie, Karl-Franzens-University, Universitätsplatz 4, Graz A-8010, Austria;6. Departamento de Farmacia y Tecnología Farmacéutica, University of Valencia, Valencia E-46000, Spain;7. School of Pharmaceutical Sciences, Pharmaceutical Biochemistry, University of Geneva, Quai Ernest-Ansermet 30, Geneva CH-1211, Switzerland;1. Botswana Institute for Technology Research and Innovation, Private Bag 0082, Gaborone, Botswana;2. Department of Biological Sciences, University of Botswana, Private Bag 00704, Gaborone, Botswana |
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| Abstract: | A series of (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives was designed, synthesized, and evaluated as novel inhibitors of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes. Most of the synthesized compounds demonstrated good inhibition activities against DPP-4. Among these, compounds 3e, 4c, 4l, and 4n exhibited prominent inhibition activities against DPP-4, with IC50s of 0.07, 0.07, 0.14, and 0.17 μM, respectively. The possible binding modes of compounds 3e and 4n with dipeptidyl peptidase-4 were also explored by molecular docking simulation. These potent DPP-4 inhibitors were optimized for the absorption, distribution, metabolism, and excretion (ADME) properties, and compound 4n displayed an attractive pharmacokinetic profile (F = 96.3%, t1/2 = 10.5 h). |
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| Keywords: | DPP-4 Type 2 diabetes Inhibitor Binding mode Oral bioavailability |
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