Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group
| Autor: | Daisuke Yamamoto, Akira Hiratate, Tomomichi Chonan, Miyoko Yashiro, Daisuke Wakasugi, Fusayo Io, Hiroko Koretsune, Hiroaki Tanaka, Ayumi Ohoka-Sugita, Takahiro Oi |
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| Rok vydání: | 2010 |
| Předmět: |
Stereochemistry
Formic Acid Esters Clinical Biochemistry Pharmaceutical Science Administration Oral Biochemistry Piperazines chemistry.chemical_compound Structure-Activity Relationship Piperidines Oral administration Drug Discovery Acid stable Animals Molecular Biology Piperazine Fatty acid synthesis Molecular Structure Organic Chemistry Stereoisomerism Fluorine Acetyl-CoA Carboxylase 1 Rats Orally active chemistry TRIF Molecular Medicine Piperidine Acetyl-CoA Carboxylase |
| Zdroj: | Bioorganicmedicinal chemistry. 19(5) |
| ISSN: | 1464-3391 |
| Popis: | Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration. |
| Databáze: | OpenAIRE |
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