Structural development of 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid derivatives as human peroxisome proliferator-activated receptor alpha (PPARα)-selective agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 29; no. 16; pp. 2124 - 2128
• Main Authors: Miyachi, Hiroyuki, Yuzuriha, Tomohiro, Tabata, Ryotaro, Fukuda, Syohei, Nunomura, Kazuto, Lin, Bangzhong, Kobayashi, Tadayuki, Ishimoto, Kenji, Doi, Takefumi, Tachibana, Keisuke
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2019; Elsevier
• Subjects: 1H-Pyrazolo-[3,4-b]pyridine-4-carboxylic acid; Agonist; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Peroxisome proliferator-activated receptor alpha; Pharmacology & Pharmacy; Physical Sciences; PPAR; PPARα agonist; Science & Technology; Structure-activity relationship; Peroxisome proliferator-activated receptor alpha; 1H-Pyrazolo-[3,4-b]pyridine-4-carboxylic acid; Agonist; PPAR; PPARα agonist; Structure-activity relationship; PPAR alpha agonist; PPAR-ALPHA; METABOLISM; BINDING; STRUCTURE-BASED DESIGN
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.06.062

[Display omitted] 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.