Structural development of 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid derivatives as human peroxisome proliferator-activated receptor alpha (PPARα)-selective agonists
| Autor: | Kazuto Nunomura, Kenji Ishimoto, Syohei Fukuda, Takefumi Doi, Keisuke Tachibana, Ryotaro Tabata, Hiroyuki Miyachi, Tomohiro Yuzuriha, Bangzhong Lin, Tadayuki Kobayashi |
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| Rok vydání: | 2019 |
| Předmět: |
Agonist
Stereochemistry medicine.drug_class Pyridines Carboxylic acid Clinical Biochemistry Substituent Pharmaceutical Science Peroxisome proliferator-activated receptor 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Pyridine medicine Structure–activity relationship Humans PPAR alpha Receptor Molecular Biology chemistry.chemical_classification Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry Molecular Medicine Peroxisome proliferator-activated receptor alpha |
| Zdroj: | Bioorganicmedicinal chemistry letters. 29(16) |
| ISSN: | 1464-3405 |
| Popis: | We previously reported that 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid derivative 6 is an agonist of human peroxisome proliferator-activated receptor alpha (hPPARα). Here, we prepared a series of 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid derivatives in order to examine the structure-activity relationships (SAR). SAR studies clearly indicated that the steric bulkiness of the substituent on 1H-pyrazolo-[3,4-b]pyridine ring, the position of the distal hydrophobic tail part, and the distance between the distal hydrophobic tail part and the acidic head part are critical for hPPARα agonistic activity. These SAR results are somewhat different from those reported for fibrate-class hPPARα agonists. A representative compound (10f) was as effective as fenofibrate in reducing the elevated plasma triglyceride levels in a high-fructose-fed rat model. |
| Databáze: | OpenAIRE |
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