Heparanase-1 (HPSE1) is an endo-β-d-glucuronidase that catalyzes degradation of heparan sulfate proteoglycans. Inhibition of HPSE1 appears to be a useful therapeutic target against cancer and proteinuric kidney diseases. We previously reported tetrahydroimidazo[1,2-a]pyridine 2 as a potent HPSE1 inhibitor after optimization of the synthetic reaction. However, synthesis of 2 involves a total of 19 steps, including a cyclization process that accompanies a strong odor due to the use of Lawesson’s reagent and an epimerization reaction; furthermore, 2 exhibited insufficient selectivity for HPSE1 over exo-β-d-glucuronidase (GUSβ) and glucocerebrosidase (GBA), which also needed to be addressed. First, the cyclization reaction was optimized to synthesize tetrahydroimidazo[1,2-a]pyridine without using Lawesson’s reagent or epimerization, with reference to previous reports. Next, 16 and 17 containing a bulkier substituent at position 6 than the 6-methoxyl group in 2 were designed and synthesized using the improved cyclization conditions, so that the synthetic route of 16 and 17 was shortened by five steps as compared with that of 2. The inhibitory activities of 16 and 17 against GUSβ and GBA were reduced as compared with those of 2, that is, the compounds showed improved selectivity for HPSE1 over GUSβ and GBA. In addition, 16 showed enhanced inhibitory activity against HPSE1 as compared with that of 2. Compound 16 appears promising as an HPSE1 inhibitor with therapeutic potential due to its highly potent inhibitory activity against HPSE1 with high selectivity for HPSE1.

Heparanase-1 (HPSE1) 是一种内切-β- d-葡萄糖醛酸酶，可催化硫酸乙酰肝素蛋白聚糖的降解。HPSE1 的抑制似乎是对抗癌症和蛋白尿肾病的有用治疗靶点。我们之前报道了在优化合成反应后，四氢咪唑并[1,2- a ]吡啶2作为有效的 HPSE1 抑制剂。然而，2的合成总共需要19个步骤，其中包括由于使用Lawesson试剂而伴随着强烈气味的环化过程以及差向异构化反应；此外，2对HPSE1相对于外切-β- d-葡萄糖醛酸酶（GUSβ）和葡萄糖脑苷脂酶（GBA）的选择性不足，这也需要解决。首先，参考前人报道，优化环化反应，在不使用Lawesson试剂或差向异构的情况下合成四氢咪唑并[1,2- a ]吡啶。接下来，采用改进的环化条件设计合成了6位取代基比2中的6-甲氧基大的16和17 ，使得16和17的合成路线比2缩短了5步。与2相比，16和17对GUSβ和GBA的抑制活性降低，即，这些化合物对HPSE1的选择性优于GUSβ和GBA。另外，与2相比，16显示出对HPSE1的抑制活性增强。化合物16由于其对 HPSE1 的高效抑制活性和对 HPSE1 的高选择性，因此有望成为具有治疗潜力的 HPSE1 抑制剂。