Mylari B L, Zembrowski W J, Beyer T A, Aldinger C E, Siegel T W
Department of Medicinal Chemistry, Pfizer Inc, Groton, Connecticut 06340.
J Med Chem. 1992 Jun 12;35(12):2155-62. doi: 10.1021/jm00090a002.
Benzothiazole side chains featured in zopolrestat (1a) and its congeners were incorporated into oxophthalazineacetic acid replacements, including indazole, pyridazinone, and pyridopyridazinone with a pendant acetic acid moiety. Potent aldose reductase inhibition activity among resulting compounds is as widespread as it is in the earlier zopolrestat series, thus lending further support to our hypothesis that there is a binding site on the aldose reductase enzyme with strong affinity for benzothiazoles. Representative new compounds 1-[(5,7-difluoro-2-benzothiazolyl)-methyl]-1H-indazoleacetic acid (62), [6-[[5-(trifluoromethyl)benzothiazol-2-yl]methyl]-8-oxo- 6H-pyrido[2,3-d]-pyridazin-5-yl]acetic acid (70), 3,4-dihydro-4-oxo-5,6-dimethyl-3-[(5,7-difluorobenzothiazol-2-yl) methyl]-1-pyridazineacetic acid (79), and 3,4-dihydro-4-oxo-5,6-cyclohexano-3-[[5-(trifluoromethyl) benzothiazol-2-yl]-methyl]-1-pyridazineacetic acid (82) are potent aldose reductase inhibitors with IC50s of 30, 2.1, 5, and 52.2 nM, respectively. The best of these compounds, 79 and 82, also inhibit accumulation of sorbitol in rat sciatic nerve in a model of diabetic complications, when administered orally at 10 mg/kg. The inhibition values are 76 and 61%, respectively. In addition to benzothiazole, we have examined its surrogates effective in potentiating aldose reductase inhibition activity, including benzoxazole and aryl[1,2,4]oxadiazole. Structure-activity relationships emerging from this program are also discussed.
将唑泊司他（1a）及其类似物中的苯并噻唑侧链引入氧代酞嗪乙酸替代物中，包括带有乙酸侧链的吲唑、哒嗪酮和吡啶并哒嗪酮。所得化合物中普遍具有较强的醛糖还原酶抑制活性，这与早期的唑泊司他系列情况相同，从而进一步支持了我们的假设，即醛糖还原酶上存在一个对苯并噻唑具有强亲和力的结合位点。代表性的新化合物1-[(5,7-二氟-2-苯并噻唑基)-甲基]-1H-吲唑乙酸（62）、[6-[[5-(三氟甲基)苯并噻唑-2-基]甲基]-8-氧代-6H-吡啶并[2,3-d]哒嗪-5-基]乙酸（70）、3,4-二氢-4-氧代-5,6-二甲基-3-[(5,7-二氟苯并噻唑-2-基)甲基]-1-哒嗪乙酸（79）和3,4-二氢-4-氧代-5,6-环己基-3-[[5-(三氟甲基)苯并噻唑-2-基]甲基]-1-哒嗪乙酸（82）均为强效醛糖还原酶抑制剂，其IC50分别为30、2.1、5和52.2 nM。这些化合物中效果最佳的79和82，在糖尿病并发症模型中以10 mg/kg口服给药时，也能抑制大鼠坐骨神经中山梨醇的积累。抑制率分别为76%和61%。除了苯并噻唑，我们还研究了其在增强醛糖还原酶抑制活性方面有效的替代物，包括苯并恶唑和芳基[1,2,4]恶二唑。还讨论了该研究项目中出现的构效关系。
