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1-Hydroxypyrazole as a bioisostere of the acetic acid moiety in a series of aldose reductase inhibitors
Therapeutic intervention with aldose reductase inhibitors appears to be promising for major pathological conditions (i.e., long-term diabetic complications and inflammatory pathologies). So far, however, clinical candidates have failed due to adverse side-effects (spiroimides) or poor bioavailabilit...
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| Published in: | Bioorganic & medicinal chemistry 2013-09, Vol.21 (17), p.4951-4957 |
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| Main Authors: | , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-c410t-88f3eb685380341df4f18107cc483ab2e100631936a5294c86e6b32f6c89cfa93 |
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| cites | cdi_FETCH-LOGICAL-c410t-88f3eb685380341df4f18107cc483ab2e100631936a5294c86e6b32f6c89cfa93 |
| container_end_page | 4957 |
| container_issue | 17 |
| container_start_page | 4951 |
| container_title | Bioorganic & medicinal chemistry |
| container_volume | 21 |
| creator | Papastavrou, Nikolaos Chatzopoulou, Maria Pegklidou, Kyriaki Nicolaou, Ioannis |
| description | Therapeutic intervention with aldose reductase inhibitors appears to be promising for major pathological conditions (i.e., long-term diabetic complications and inflammatory pathologies). So far, however, clinical candidates have failed due to adverse side-effects (spiroimides) or poor bioavailability (carboxylic acids). In this work, we succeeded in the bioisosteric replacement of an acetic acid moiety with that of 1-hydroxypyrazole. This new scaffold appears to have a superior physicochemical profile, while attaining inhibitory activity in the submicromolar range. |
| doi_str_mv | 10.1016/j.bmc.2013.06.062 |
| format | article |
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So far, however, clinical candidates have failed due to adverse side-effects (spiroimides) or poor bioavailability (carboxylic acids). In this work, we succeeded in the bioisosteric replacement of an acetic acid moiety with that of 1-hydroxypyrazole. This new scaffold appears to have a superior physicochemical profile, while attaining inhibitory activity in the submicromolar range.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2013.06.062</identifier><identifier>PMID: 23891165</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>acetic acid ; Acetic Acid - chemistry ; adverse effects ; aldehyde reductase ; Aldehyde Reductase - antagonists & inhibitors ; Aldehyde Reductase - metabolism ; Aldose reductase inhibitors ; Animals ; bioavailability ; Bioisosterism ; chemistry ; diabetic complications ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - metabolism ; Inflammatory pathologies ; Kidney - enzymology ; Kinetics ; Lens Cortex, Crystalline - enzymology ; Long-term diabetic complications ; Molecular obesity ; Protein Binding ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - metabolism ; Rats ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry, 2013-09, Vol.21 (17), p.4951-4957</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. 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| fulltext | fulltext |
| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2013-09, Vol.21 (17), p.4951-4957 |
| issn | 0968-0896 1464-3391 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1500791397 |
| source | ScienceDirect Journals |
| subjects | acetic acid Acetic Acid - chemistry adverse effects aldehyde reductase Aldehyde Reductase - antagonists & inhibitors Aldehyde Reductase - metabolism Aldose reductase inhibitors Animals bioavailability Bioisosterism chemistry diabetic complications Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Inflammatory pathologies Kidney - enzymology Kinetics Lens Cortex, Crystalline - enzymology Long-term diabetic complications Molecular obesity Protein Binding Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - metabolism Rats Structure-Activity Relationship |
| title | 1-Hydroxypyrazole as a bioisostere of the acetic acid moiety in a series of aldose reductase inhibitors |
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