| Structural modifications of (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid, a potent irreversible inhibitor of GABA aminotransferase. | |
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MedLine Citation:
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PMID: 17267220 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Low brain levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) lead to convulsions. Inhibition of GABA aminotransferase increases the concentration of GABA and can terminate the convulsions. Earlier we reported the synthesis of (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid (2), which is 186 times more potent an inactivator of GABA aminotransferase than the epilepsy drug S-vigabatrin. The corresponding dichloromethylene analogue of 2 (compound 3) has been made, but it shows only weak reversible inhibition of GABA aminotransferase. However, the tetrazole isostere of 2 (compound 4) has been found to be a time-dependent inactivator of GABA aminotransferase. Although it is 20 times less potent than carboxylic acid 2, it is 2.5 times more potent than S-vigabatrin. A calculation of the ClogP values indicates that 4 is the most lipophilic of the three, being 69 times more lipophilic than 2 and 55 times more lipophilic than S-vigabatrin, indicating potential for improved bioavailability. |
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Authors:
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Hai Yuan; Richard B Silverman |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-01-17 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: 17 ISSN: 0960-894X ISO Abbreviation: Bioorg. Med. Chem. Lett. Publication Date: 2007 Mar |
Date Detail:
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Created Date: 2007-02-23 Completed Date: 2007-05-29 Revised Date: 2010-09-20 |
Medline Journal Info:
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Nlm Unique ID: 9107377 Medline TA: Bioorg Med Chem Lett Country: England |
Other Details:
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Languages: eng Pagination: 1651-4 Citation Subset: IM |
Affiliation:
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Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL 60208-3113, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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4-Aminobutyrate Transaminase
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antagonists & inhibitors* Carboxylic Acids / chemical synthesis*, pharmacology* Chemistry, Physical Cyclopentanes / chemical synthesis*, pharmacology* Enzyme Inhibitors / chemical synthesis*, chemistry, pharmacology* Kinetics Physicochemical Phenomena Structure-Activity Relationship |
| Grant Support | |
ID/Acronym/Agency:
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GM 66132/GM/NIGMS NIH HHS; R01 GM066132-04/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/(1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid; 0/Carboxylic Acids; 0/Cyclopentanes; 0/Enzyme Inhibitors; EC 2.6.1.19/4-Aminobutyrate Transaminase |
| Comments/Corrections | |
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