新穎免疫抑制劑leflunomide之藥理作用及其結構修飾

自體免疫疾病的治療常因疾病惡化程度加劇，伴隨不適及病人對藥物耐受性而放棄用藥等挑戰，成為治療上需突破的重要課題。本文回顧免疫抑制用藥並詳述新穎免疫抑制劑leflunomide（1）的藥理作用及其新衍生物的結構修飾。美國FDA於1998年核准上市之新藥leflunomide（1），明顯地較以往之免疫抑制劑之預後為佳及副作用小，是最新用於治療類風濕關節炎的疾病修飾藥物。其化學結構為異噁唑衍生物，為一前驅藥物，於體內快速地被代謝為活性代謝物（丙二醯腈醯胺）；藥理作用主要抑制dihydroorotate dehydrogenase和tyrosine kinases，因而阻抑T細胞的增生，達到免疫抑制的效果。利用leflunomide（1）為基礎的藥物設計及結構修飾，除可增強療效，減少副作用外，更具有抗發炎、乳癌、白血病、器官移植的排斥反應和鎮痛等效果。

關鍵字

風濕疾病修飾藥；免疫抑制劑；類風濕關節炎

並列摘要

The challenges associated with the treatment of autoimmune disease are dependent on the degree of disease progression, concomitant conditions, and tolerability and withdrawn uses of drugs. This article briefly reviews immunosuppresants and focusely describe leflunomide and its analogs on structural modifications. Leflunomide, approved by the FDA in 1998 for the treatment of moderate to severe active rhematoid arthritis, is a novel immunomodulating agent that exhibits antiproliferative activity in significantly improved safety and effectiveness as a disease modifying anti-rheumatoid arthritis drug. Leflunomide is a prodrug readily metabolized to the active metabolite, malononitrilamide, which has whose pharmacological activity is mediated through dual mechanisms by reversible inhibition of the enzyme dihydroorotate dehydrogenase and inhibition of tyrosine kinases. The new drug design and structural modification based on leflunomide yield a variety of compounds with higher potency and less toxicity, and beneficial therapeutic uses for anti-inflammatory, anti-human breast cancer, anti-leukema, anti-graft rejection, and analgesic as well.

並列關鍵字

disease-modifying anti-rheumatoid arthritis drug ； immunosuppressarnt ； leflunomide ； rheumatoid arthritis

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新穎免疫抑制劑leflunomide之藥理作用及其結構修飾

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