Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Bioorg Med Chem Lett. 2019 Aug 15;29(16):2124-2128. doi: 10.1016/j.bmcl.2019.06.062. Epub 2019 Jul 4.
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.
我们之前曾报道过 1H-吡唑并[3,4-b]吡啶-4-羧酸衍生物 6 是人类过氧化物酶体增殖物激活受体 α（hPPARα）的激动剂。在这里，我们制备了一系列 1H-吡唑并[3,4-b]吡啶-4-羧酸衍生物，以研究构效关系（SAR）。SAR 研究清楚地表明，1H-吡唑并[3,4-b]吡啶环上取代基的空间位阻、远端疏水性尾部部分的位置以及远端疏水性尾部部分与酸性头部部分之间的距离对 hPPARα激动活性至关重要。这些 SAR 结果与报道的纤维酸类 hPPARα 激动剂有些不同。代表性化合物（10f）在降低高果糖喂养大鼠模型中升高的血浆甘油三酯水平方面与非诺贝特一样有效。
