Imidazole-derived agonists for the neurotensin 1 receptor |
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| Affiliation: | 1. Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA;2. Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA;3. Duke University Medical Center, Durham, NC 27710, USA;4. RTI International, 3040 E Cornwallis Road, Durham, NC 27709, USA;1. Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;2. Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;3. Sanford Children’s Health Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;4. The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, UK;1. GlaxoSmithKline, Antiviral Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA;2. GlaxoSmithKline, Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, USA;3. GlaxoSmithKline, Anti Bacterial Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA;1. WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People’s Republic of China;2. Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, People''s Republic of China;1. Medicinal Chemistry, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States;2. Computational Sciences and Crystallography, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States;3. Discovery Biology, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States;1. Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine;2. Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science, 1 Murmanska, Kyiv 02660, Ukraine;3. Taras Shevchenko National University, 62 Volodymyrska, Kyiv 01033, Ukraine;4. Institute of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof 198504, Russian Federation |
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| Abstract: | ![]()
A scaffold-hop program seeking full agonists of the neurotensin-1 (NTR1) receptor identified the probe molecule ML301 (1) and associated analogs, including its naphthyl analog (14) which exhibited similar properties. Compound 1 showed full agonist behavior (79–93%) with an EC50 of 2.0–4.1 μM against NTR1. Compound 1 also showed good activity in a Ca mobilization FLIPR assay (93% efficacy at 298 nM), consistent with it functioning via the Gq coupled pathway, and good selectivity relative to NTR2 and GPR35. In further profiling, 1 showed low potential for promiscuity and good overall pharmacological data. This report describes the discovery, synthesis, and SAR of 1 and associated analogs. Initial in vitro pharmacologic characterization is also presented. |
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| Keywords: | Imidazole Neurotensin 1 Agonist Methamphetamine |
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