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

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

  • Bioorg Med Chem Lett. 2019 Aug 15;29(16):2124-2128. doi: 10.1016/j.bmcl.2019.06.062.
Hiroyuki Miyachi 1,  Tomohiro Yuzuriha 2,  Ryotaro Tabata 2,  Syohei Fukuda 2,  Kazuto Nunomura 2,  Bangzhong Lin 2,  Tadayuki Kobayashi 2,  Kenji Ishimoto 2,  Takefumi Doi 2,  Keisuke Tachibana 2
Affiliations

Affiliations

  • 1 Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
  • 2 Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
PMID: 31320147 DOI: 10.1016/j.bmcl.2019.06.062
Abstract

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.

Keywords

1H-Pyrazolo-[3,4-b]pyridine-4-carboxylic acid; Agonist; PPAR; PPARα agonist; Peroxisome proliferator-activated receptor alpha; Structure-activity relationship.

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