Small Molecule Drug Research Laboratories, R&D Division, Kyowa Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
Immunology & Allergy Research Laboratories, R&D Division, Kyowa Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
Bioorg Med Chem. 2020 Sep 1;28(17):115622. doi: 10.1016/j.bmc.2020.115622. Epub 2020 Jul 14.
We previously reported 2-aminobenzoxazole analogue 1 as a potent ChemR23 inhibitor. The compound showed inhibitory activity against chemerin-induced calcium signaling through ChemR23 internalization in CAL-1 cells, which are cell lines of plasmacytoid dendric cells (pDCs). Furthermore, compound 2 inhibited chemotaxis of CAL-1 triggered by chemerin in vitro. However, we noted a difference in the ChemR23 response to our inhibitor between rodents and non-rodents in a previous study. To address this issue, we performed optimization of ChemR23 inhibitors using CAL-1 cells endogenously expressing human ChemR23 and conducted a pharmacokinetics study in cynomolgus monkeys. Various substituents at the 4-position of the benzoxazole ring exhibited potent in vitro bioactivity, while those at the 6-position were not tolerated. Among substituents, a carboxyl group was identified as key for improving the oral bioavailability in cynomolgus monkeys. Compound 38a with the acidic part changed from a tetrazole group to a 1,2,4-oxadiazol-5-one group to improve bioactivity and pharmacokinetic parameters exhibited inhibitory activity against chemerin-induced chemotaxis in vitro. In addition, we confirmed the ChemR23 internalization of pDCs by compound 38a orally administered to cynomolgus monkeys. These 2-aminobenzoxazole-based ChemR23 inhibitors may be useful as novel immunotherapeutic agents capable of suppressing the migration of pDCs, which are known to be major producers of type I interferons in the lesion area of certain autoimmune diseases, such as systemic lupus erythematosus and psoriasis.
我们之前报道过 2-氨基苯并恶唑类似物 1 是一种有效的 ChemR23 抑制剂。该化合物通过 ChemR23 内化显示出对趋化素诱导的钙信号的抑制活性，在 CAL-1 细胞（浆细胞样树突状细胞（pDC）的细胞系）中。此外，化合物 2 抑制趋化素诱导的 CAL-1 体外趋化性。然而，在之前的研究中，我们注意到我们的抑制剂在啮齿动物和非啮齿动物中的 ChemR23 反应存在差异。为了解决这个问题，我们使用内源性表达人 ChemR23 的 CAL-1 细胞对 ChemR23 抑制剂进行了优化，并在食蟹猴中进行了药代动力学研究。苯并恶唑环 4 位的各种取代基表现出很强的体外生物活性，而 6 位的取代基则不能耐受。在取代基中，确定羧基是提高食蟹猴口服生物利用度的关键。具有酸性部分的化合物 38a 将三唑基团改变为 1,2,4-噁二唑-5-酮基团，以提高生物活性和药代动力学参数，对趋化素诱导的体外趋化性表现出抑制活性。此外，我们通过食蟹猴口服化合物 38a 证实了 pDC 的 ChemR23 内化。这些基于 2-氨基苯并恶唑的 ChemR23 抑制剂可用作新型免疫治疗剂，能够抑制 pDC 的迁移，pDC 是某些自身免疫性疾病（如系统性红斑狼疮和银屑病）病变区域中 I 型干扰素的主要产生者。
