Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake
We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repos...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2017
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| Online Access: | http://hdl.handle.net/1721.1/106851 https://orcid.org/0000-0003-2673-1672 https://orcid.org/0000-0003-4541-5181 |
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| author | Dockendorff, Chris Faloon, Patrick W. Pu, Jun Johnston, Stephen Bennion, Melissa Dandapani, Sivaraman Perez, José R. Munoz, Benito Palmer, Michelle A. Schreiber, Stuart L. Yu, Miao Penman, Marsha L Nieland, Thomas J Krieger, Monty |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Dockendorff, Chris Faloon, Patrick W. Pu, Jun Johnston, Stephen Bennion, Melissa Dandapani, Sivaraman Perez, José R. Munoz, Benito Palmer, Michelle A. Schreiber, Stuart L. Yu, Miao Penman, Marsha L Nieland, Thomas J Krieger, Monty |
| author_sort | Dockendorff, Chris |
| collection | MIT |
| description | We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR), measuring the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure–activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogs prepared via solution phase synthesis. These studies demonstrate that the orientation of the substituents on the aliphatic ring have a critical effect on activity. Additionally, a lipophilic group is required at the western end of the molecule, and a northern hydroxyl group and a southern sulfonamide substituent also proved to be optimal. Compound 2p was found to possess a superior combination of potency (av IC[subscript 50] = 0.10 μM) and solubility (79 μM in PBS), and it was designated as probe ML312. |
| first_indexed | 2024-09-23T09:48:58Z |
| format | Article |
| id | mit-1721.1/106851 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:48:58Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1068512022-09-30T17:02:17Z Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake Dockendorff, Chris Faloon, Patrick W. Pu, Jun Johnston, Stephen Bennion, Melissa Dandapani, Sivaraman Perez, José R. Munoz, Benito Palmer, Michelle A. Schreiber, Stuart L. Yu, Miao Penman, Marsha L Nieland, Thomas J Krieger, Monty Massachusetts Institute of Technology. Department of Biology Yu, Miao Penman, Marsha L Nieland, Thomas J Krieger, Monty We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR), measuring the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure–activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogs prepared via solution phase synthesis. These studies demonstrate that the orientation of the substituents on the aliphatic ring have a critical effect on activity. Additionally, a lipophilic group is required at the western end of the molecule, and a northern hydroxyl group and a southern sulfonamide substituent also proved to be optimal. Compound 2p was found to possess a superior combination of potency (av IC[subscript 50] = 0.10 μM) and solubility (79 μM in PBS), and it was designated as probe ML312. 2017-02-03T16:20:33Z 2017-02-03T16:20:33Z 2015-04 2015-03 Article http://purl.org/eprint/type/JournalArticle 0960-894X http://hdl.handle.net/1721.1/106851 Dockendorff, Chris et al. “Benzo-Fused Lactams from a Diversity-Oriented Synthesis (DOS) Library as Inhibitors of Scavenger Receptor BI (SR-BI)-Mediated Lipid Uptake.” Bioorganic & Medicinal Chemistry Letters 25.10 (2015): 2100–2105. https://orcid.org/0000-0003-2673-1672 https://orcid.org/0000-0003-4541-5181 en_US http://dx.doi.org/10.1016/j.bmcl.2015.03.073 Bioorganic & Medicinal Chemistry Letters Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Dockendorff, Chris Faloon, Patrick W. Pu, Jun Johnston, Stephen Bennion, Melissa Dandapani, Sivaraman Perez, José R. Munoz, Benito Palmer, Michelle A. Schreiber, Stuart L. Yu, Miao Penman, Marsha L Nieland, Thomas J Krieger, Monty Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake |
| title | Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake |
| title_full | Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake |
| title_fullStr | Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake |
| title_full_unstemmed | Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake |
| title_short | Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake |
| title_sort | benzo fused lactams from a diversity oriented synthesis dos library as inhibitors of scavenger receptor bi sr bi mediated lipid uptake |
| url | http://hdl.handle.net/1721.1/106851 https://orcid.org/0000-0003-2673-1672 https://orcid.org/0000-0003-4541-5181 |
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