Design of a new series of potent and selective beta-3 adrenergic receptor (β3-AdrR) antagonists for the treatment of acute decompensated heart failure
The design of a new series of β3-Adrenergic receptor (β3-AdrR) antagonists is described. The use of a spiro building block in the core of the molecule provided novel compounds with reduced aromaticity and antagonist activity at the human β3-AdrR. A shortening of this core and exploration of a series...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-01-01
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| Series: | Results in Chemistry |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211715622002375 |
| _version_ | 1798006248385282048 |
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| author | Thuy-Anh Tran Bryan Kramer Young-Jun Shin Quyen-Quyen Do Brett Ullman Vasudeva Sagi John W. Adams Yunqing Shi Hsin-Hui Shu David J. Unett Joel Gatlin Michael E. Morgan Jaimie Reuter Anthony Blackburn Carleton R. Sage Graeme Semple |
| author_facet | Thuy-Anh Tran Bryan Kramer Young-Jun Shin Quyen-Quyen Do Brett Ullman Vasudeva Sagi John W. Adams Yunqing Shi Hsin-Hui Shu David J. Unett Joel Gatlin Michael E. Morgan Jaimie Reuter Anthony Blackburn Carleton R. Sage Graeme Semple |
| author_sort | Thuy-Anh Tran |
| collection | DOAJ |
| description | The design of a new series of β3-Adrenergic receptor (β3-AdrR) antagonists is described. The use of a spiro building block in the core of the molecule provided novel compounds with reduced aromaticity and antagonist activity at the human β3-AdrR. A shortening of this core and exploration of a series of sulfonamide derivatives produced compounds with good selectivity over β1-AdrR and β2-AdrR. Alternative substitutions on the terminal aromatic rings produced compounds with further improvements in selectivity, particularly with respect to β2-AdrR. Finally, the incorporation of heteroatoms into the fused aromatic ring provided significant improvements in solubility. One compound from the series was shown to antagonize the effect of an exogenously administered β3-AdrR agonist on left ventricular pressure in the rat, making this a series of high interest for further Lead Optimization. |
| first_indexed | 2024-04-11T12:51:45Z |
| format | Article |
| id | doaj.art-6533cc49f4b54ba9916eb28cfabb9af8 |
| institution | Directory Open Access Journal |
| issn | 2211-7156 |
| language | English |
| last_indexed | 2024-04-11T12:51:45Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Results in Chemistry |
| spelling | doaj.art-6533cc49f4b54ba9916eb28cfabb9af82022-12-22T04:23:10ZengElsevierResults in Chemistry2211-71562022-01-014100518Design of a new series of potent and selective beta-3 adrenergic receptor (β3-AdrR) antagonists for the treatment of acute decompensated heart failureThuy-Anh Tran0Bryan Kramer1Young-Jun Shin2Quyen-Quyen Do3Brett Ullman4Vasudeva Sagi5John W. Adams6Yunqing Shi7Hsin-Hui Shu8David J. Unett9Joel Gatlin10Michael E. Morgan11Jaimie Reuter12Anthony Blackburn13Carleton R. Sage14Graeme Semple15Eurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAEurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USACorresponding author.; Eurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, CA 92121, USAThe design of a new series of β3-Adrenergic receptor (β3-AdrR) antagonists is described. The use of a spiro building block in the core of the molecule provided novel compounds with reduced aromaticity and antagonist activity at the human β3-AdrR. A shortening of this core and exploration of a series of sulfonamide derivatives produced compounds with good selectivity over β1-AdrR and β2-AdrR. Alternative substitutions on the terminal aromatic rings produced compounds with further improvements in selectivity, particularly with respect to β2-AdrR. Finally, the incorporation of heteroatoms into the fused aromatic ring provided significant improvements in solubility. One compound from the series was shown to antagonize the effect of an exogenously administered β3-AdrR agonist on left ventricular pressure in the rat, making this a series of high interest for further Lead Optimization.http://www.sciencedirect.com/science/article/pii/S2211715622002375GPCRβ3-Adrenergic receptorβ3-AdrRAntagonistAcute decompensated heart failure |
| spellingShingle | Thuy-Anh Tran Bryan Kramer Young-Jun Shin Quyen-Quyen Do Brett Ullman Vasudeva Sagi John W. Adams Yunqing Shi Hsin-Hui Shu David J. Unett Joel Gatlin Michael E. Morgan Jaimie Reuter Anthony Blackburn Carleton R. Sage Graeme Semple Design of a new series of potent and selective beta-3 adrenergic receptor (β3-AdrR) antagonists for the treatment of acute decompensated heart failure Results in Chemistry GPCR β3-Adrenergic receptor β3-AdrR Antagonist Acute decompensated heart failure |
| title | Design of a new series of potent and selective beta-3 adrenergic receptor (β3-AdrR) antagonists for the treatment of acute decompensated heart failure |
| title_full | Design of a new series of potent and selective beta-3 adrenergic receptor (β3-AdrR) antagonists for the treatment of acute decompensated heart failure |
| title_fullStr | Design of a new series of potent and selective beta-3 adrenergic receptor (β3-AdrR) antagonists for the treatment of acute decompensated heart failure |
| title_full_unstemmed | Design of a new series of potent and selective beta-3 adrenergic receptor (β3-AdrR) antagonists for the treatment of acute decompensated heart failure |
| title_short | Design of a new series of potent and selective beta-3 adrenergic receptor (β3-AdrR) antagonists for the treatment of acute decompensated heart failure |
| title_sort | design of a new series of potent and selective beta 3 adrenergic receptor β3 adrr antagonists for the treatment of acute decompensated heart failure |
| topic | GPCR β3-Adrenergic receptor β3-AdrR Antagonist Acute decompensated heart failure |
| url | http://www.sciencedirect.com/science/article/pii/S2211715622002375 |
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