Discovery of novel sulfonamides as potent and selective inhibitors against human and mouse 11β-hydroxysteroid dehydrogenase type 1

Several classes of non-steroid 11β-HSD1 inhibitors have been developed as promising treatments for Type 2 Diabetes (T2D). Using a human 11β-HSD1 selective inhibitor as a starting point, we designed and synthesized a new class of derivatives of 1-arylsulfonyl piperidine-3-carboxamides. It was found that the large lipophilic group on the amino moiety may lead to cross-species potency towards human and mouse, allowing drug development by evaluating compounds in rodent model. By exploring structure-activity-relationship, the (R)-(+)-bornylamine derivative is identified as the most potent inhibitor of mouse enzyme 11β-HSD1 with an IC(50) of 18 nM. Docking studies revealed the different possible interaction modes of the S-enantiomer and R-enantiomer bound to h11β-HSD1, and explained why the S-enantiomer is more active than the R-enantiomer. Finally, two potent and isoform-selective compounds, (+)-isopinocampheylamine derivative 8m and (R)-(+)-bornylamine derivative 8l, with suitable in vitro properties, could be selected for future PK/PD evaluation in rodent models. Then, 8l was subjected a pharmacodynamics study in vivo with rodent model. It was shown that 8l have 71% and 63% inhibition in adipose and liver tissue at 1h after administration, but it was a short-acting compound displaying a significant drop in potency in the subsequent 3h. This study not only provides compounds as novel h11β-HSD1 inhibitors, but also presents structure-activity relationships for designing potent human/mouse 11β-HSD1 inhibitors suitable for in vivo evaluation in rodent models.     

可注射型热触发仿天然骨材料的基础研究

目的：试图研制可注射型热敏仿天然骨材料,测定其理化特性,并将其初步应用于体外根尖孔破坏的离体牙模型上。方法：采用逆向蒸发法制备载碱性磷酸酶（alkalinephosphatase,ALP）的脂质体,考察其包封率、活性率及相变温度。将载ALP、载钙离子（Ca^24）和磷酸盐（Pi）3种脂质体与β-甘油磷酸盐（β-glycerophosphate,β-GP）混合制备矿化液,观测矿物质的形态、元素分析及红外光谱曲线;将I型胶原与以上矿化液混合制备的复合材料应用于根尖孔破坏的离体牙根尖周围,根管充填并统计分析。结果：载ALP的脂质体平均包封率为25．1％,平均活性率为16．5％,相变温度为37．3～40．1℃,峰值为39．2℃;与未加ALP者相比,所得矿化物形态和Ca／Pi比与天然骨中矿化物更接近,红外光谱曲线表明其为羟基磷灰石;体外模型显示该复合材料可在一定程度上支托根充材料,预防超充。