Kuo E A, Hambleton P T, Kay D P, Evans P L, Matharu S S, Little E, McDowall N, Jones C B, Hedgecock C J, Yea C M, Chan A W, Hairsine P W, Ager I R, Tully W R, Williamson R A, Westwood R
Hoechst Marion Roussel, Wiltshire, England.
J Med Chem. 1996 Nov 8;39(23):4608-21. doi: 10.1021/jm9604437.
The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.
新型免疫抑制剂来氟米特（1）的活性代谢物（2）已被证明可抑制二氢乳清酸脱氢酶（DHODH）。该酶催化从头嘧啶生物合成的第四步。已合成了一系列活性代谢物2的类似物。在大鼠和小鼠迟发型超敏反应中测定的它们的体内生物活性已被发现与其体外DHODH效力密切相关。最有前景的化合物（3）在大鼠和小鼠胶原（II）诱导的关节炎模型中显示出活性（ED50分别为2和31 mg/kg），并且与来氟米特相比，在人体内的半衰期更短。类风湿性关节炎的临床研究正在进行中。
