Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan.
Sci Rep. 2020 May 6;10(1):7623. doi: 10.1038/s41598-020-64527-x.
Small-molecule agonism of peroxisome proliferator-activated receptor α (PPARα), a ligand-activated transcriptional factor involved in regulating fatty acid metabolism, is an important approach for treating dyslipidemia. Here, we determined the structures of the ligand-binding domain (LBD) of PPARα in complex with 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives, which were recently identified as PPARα-selective activators with markedly different structures from those of the well-known PPARα agonists fibrates. The crystal structures of the complexes showed that they form a canonical hydrogen-bond network involving helix 12 in the LBD, which is thought to be essential for PPARα activation, as also observed for fibrates. However, the phenyl side chain of the compounds occupies a small cavity between Ile272 and Ile354, which is rarely accessed by fibrates. This unique feature may be essential for subtype selectivity and combine with the well-characterized binding mode of fibrates to improve activity. These findings demonstrate the advantage of using 1H-pyrazolo-[3,4-b]pyridine as a skeleton of PPARα agonists and provide insight into the design of molecules for treating dyslipidemia.
小分子激动剂的过氧化物酶体增殖物激活受体 α（PPARα），一种配体激活的转录因子，参与调节脂肪酸代谢，是治疗血脂异常的重要方法。在这里，我们确定了配体结合域（LBD）与 1H-吡唑并[3,4-b]吡啶-4-羧酸衍生物复合物的 PPARα 结构，这些衍生物最近被确定为 PPARα 选择性激动剂，其结构与众所周知的 PPARα 激动剂贝特类药物明显不同。复合物的晶体结构表明，它们形成了一个典型的氢键网络，涉及 LBD 中的螺旋 12，这被认为是 PPARα 激活所必需的，与贝特类药物的观察结果一致。然而，化合物的苯基侧链占据了 Ile272 和 Ile354 之间的一个小空腔，该空腔很少被贝特类药物占据。这种独特的特征可能对亚型选择性至关重要，并与贝特类药物的良好特征结合，以提高活性。这些发现证明了将 1H-吡唑并[3,4-b]吡啶用作 PPARα 激动剂骨架的优势，并为治疗血脂异常的分子设计提供了思路。
