抑制鞘氨醇 1-磷酸裂解酶治疗类风湿关节炎：（E）-1-（4-（（1R，2S，3R）-1，2，3，4-四羟基丁基）-1H-咪唑-2-基）乙酮肟（LX2931）和（1R，2S，3R）-1-（2-（异恶唑-3-基）-1H-咪唑-4-基）丁烷-1,2,3,4-四醇（LX2932）的发现。

Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932).

机构信息

Lexicon Pharmaceuticals, Inc., Princeton, New Jersey 08540, USA.

出版信息

J Med Chem. 2010 Dec 23;53(24):8650-62. doi: 10.1021/jm101183p. Epub 2010 Nov 22.

Abstract

Sphingosine 1-phosphate lyase (S1PL) has been characterized as a novel target for the treatment of autoimmune disorders using genetic and pharmacological methods. Medicinal chemistry efforts targeting S1PL by direct in vivo evaluation of synthetic analogues of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI, 1) led to the discovery of 2 (LX2931) and 4 (LX2932). The immunological phenotypes observed in S1PL deficient mice were recapitulated by oral administration of 2 or 4. Oral dosing of 2 or 4 yielded a dose-dependent decrease in circulating lymphocyte numbers in multiple species and showed a therapeutic effect in rodent models of rheumatoid arthritis (RA). Phase I clinical trials indicated that 2, the first clinically studied inhibitor of S1PL, produced a dose-dependent and reversible reduction of circulating lymphocytes and was well tolerated at dose levels of up to 180 mg daily. Phase II evaluation of 2 in patients with active rheumatoid arthritis is currently underway.

摘要

鞘氨醇 1-磷酸裂解酶 (S1PL) 已被确认为一种新型靶点，可通过遗传和药理学方法治疗自身免疫性疾病。通过直接对 2-乙酰-4(5)-(1(R),2(S),3(R),4-四羟基丁基)-咪唑 (THI, 1) 的合成类似物进行体内评估，针对 S1PL 的药物化学研究发现了 2 (LX2931) 和 4 (LX2932)。S1PL 缺陷小鼠的免疫表型可通过口服 2 或 4 重现。2 或 4 的口服给药可使多种物种的循环淋巴细胞数量呈剂量依赖性下降，并在类风湿关节炎 (RA) 的啮齿动物模型中显示出治疗效果。I 期临床试验表明，S1PL 的首个临床研究抑制剂 2 可产生剂量依赖性和可逆的循环淋巴细胞减少，在高达 180mg/天的剂量水平下具有良好的耐受性。目前正在进行 2 期临床试验，评估其在活动性类风湿关节炎患者中的疗效。