NOVEL, POTENT ALDOSE REDUCTASE INHIBITORS - 3,4-DIHYDRO-4-OXO-3-[[5-(TRIFLUOROMETHYL)-2-BENZOTHIAZOLYL]METHYL]-1-PHTHALAZINEACETIC ACID (ZOPOLRESTAT) AND CONGENERS
NOVEL, POTENT ALDOSE REDUCTASE INHIBITORS - 3,4-DIHYDRO-4-OXO-3-[[5-(TRIFLUOROMETHYL)-2-BENZOTHIAZOLYL]METHYL]-1-PHTHALAZINEACETIC ACID (ZOPOLRESTAT) AND CONGENERS
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DOI：
10.1021/jm00105a018
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发表时间：
1991-01-01
影响因子：
7.3
通讯作者：
SINGLETON, DH
中科院分区：
文献类型：
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作者：
MYLARI, BL;LARSON, ER;SINGLETON, DH
一个新的工作假设，有一个迄今为止尚未认识到的结合位点的醛糖还原酶（AR）与苯并噻唑具有很强的亲和力，追求设计新的，有效的醛糖还原酶抑制剂（阿里斯）。 这一假说的首次应用导致了一系列新的3，4-二氢-4-氧代-3-（苯并噻唑甲基）-1-酞嗪乙酸。 该系列的母体药物（207）是一种来自人胎盘的AR强效抑制剂（IC 50 = 1.9 x 10-8 M），在糖尿病并发症的急性试验中（ED 50 = 18.5 mg/kg），口服可有效预防大鼠坐骨神经中山梨醇蓄积。 通过药用化学原理优化该先导化合物，包括与其他药物系列的类比，得到了207的更强效同系物，最终设计出3，4-二氢-4-氧代-3-[[5-（三氟CP-73，850，唑泊司他）]。 Zopolrestat被发现在体内比207更有效。 在急性试验中，其对AR的IC 50和ED 50分别为3.1 × 10-9 M和3.6 mg/kg。 在慢性试验中，其逆转大鼠坐骨神经、视网膜和透镜中山梨醇蓄积升高的ED 50分别为1.9、17.6和18.4 mg/kg。 它在糖尿病患者中吸收良好，导致血药浓度高，显示出非常有利的血浆半衰期（27.5小时），正在进行进一步的临床评价。 分类的合成方法用于建设苯并噻唑，包括一个有效的合成zopolrestat，描述。 在新系列的结构-活性关系进行了讨论。
A new working hypothesis that there is a hitherto unrecognized binding site on the aldose reductase (AR) enzyme with strong affinity for benzothiazoles was pursued for the design of novel, potent aldose reductase inhibitors (ARIs). The first application of this hypothesis led to a novel series of 3,4-dihydro-4-oxo-3-(benzothiazolylmethyl)-1-phthalazineacetic acids. The parent of this series (207) was a potent inhibitor of AR from human placenta (IC50 = 1.9 x 10-8 M) and was orally active in preventing sorbitol accumulation in rat sciatic nerve, in an acute test of diabetic complications (ED50 = 18.5 mg/kg). Optimization of this lead through medicinal chemical rationale, including analogy from other drug series, led to more potent congeners of 207 and culminated in the design of 3,4-dihydro-4-oxo-3-[[5-(trifluorCP-73,850, zopolrestat). Zopolrestat was found to be more potent than 207, both in vivo. Its IC50 against AR and ED50 in the acute test were 3.1 x 10-9 M and 3.6 mg/kg, respectively. Its ED50s in reversing already elevated sorbitol accumulation in rat sciatic nerve, retina, and lens in a chronic test were 1.9, 17.6, and 18.4 mg/kg, respectively. It was well absorbed in diabetic patients, resulting in high blood level, showed a highly favorable plasma half-life (27.5 h), and is undergoing further clinical evaluation. An assortment of synthetic methods used for the construction of benzothiazoles, including an efficient synthesis of zopolrestat, is described. Structure-activity relationships in the new series are discussed.