Jirousek M R, Gillig J R, Gonzalez C M, Heath W F, McDonald J H, Neel D A, Rito C J, Singh U, Stramm L E, Melikian-Badalian A, Baevsky M, Ballas L M, Hall S E, Winneroski L L, Faul M M
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
J Med Chem. 1996 Jul 5;39(14):2664-71. doi: 10.1021/jm950588y.
Protein kinase C (PKC) is a family of closely related serine and threonine kinases. Overactivation of some PKC isozymes has been postulated to occur in several diseases states, including diabetic complications. Selective inhibition of overactivated PKC isozymes may offer a unique therapeutic approach to disease states such as diabetic retinopathy. A novel series of 14-membered macrocycles containing a N-N'-bridged bisindolylmaleimide moiety is described. A panel of eight cloned human PKC isozymes (alpha, beta I, beta II, gamma, delta, epsilon, sigma, eta) was used to identify the series and optimize the structure and associated activity relationship. The dimethylamine analogue LY333531 (1), (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene++ +-1,3(2H)-dione, inhibits the PKC beta I (IC50 = 4.7 nM) and PKC beta II (IC50 = 5.9 nM) isozymes and was 76- and 61-fold selective for inhibition of PKC beta I and PKC beta II in comparison to PKC alpha, respectively. The additional analogues described in the series are also selective inhibitors of PKC beta. LY333531 (1) exhibits ATP dependent competitive inhibition of PKC beta I and is selective for PKC in comparison to other ATP dependent kinases (protein kinase A, calcium calmodulin, caesin kinase, src tyrosine kinase). The cellular activity of the series was assessed using bovine retinal capillary endothelial cells. Retinal endothelial cell dysfunction has been implicated in the development of diabetic retinopathy. Plasminogen activator activity stimulated by a phorbol ester (4 beta-phorbol 12,13-dibutyrate) in endothelial cells was inhibited by the compounds in the series with ED50 values ranging from 7.5 to 0.21 microM. A comparison of the PKC isozyme and related ATP dependent kinase inhibition profiles is provided for the series and compared to the profile for staurosporine, a nonselective PKC inhibitor. The cellular activity of the series is compared with that of the kinase inhibitor staurosporine.
蛋白激酶C（PKC）是一族密切相关的丝氨酸和苏氨酸激酶。据推测，某些PKC同工酶的过度激活会在包括糖尿病并发症在内的多种疾病状态中发生。选择性抑制过度激活的PKC同工酶可能为诸如糖尿病视网膜病变等疾病状态提供一种独特的治疗方法。本文描述了一系列含有N-N'-桥连双吲哚马来酰亚胺部分的新型14元大环化合物。使用一组八个克隆的人PKC同工酶（α、βI、βII、γ、δ、ε、σ、η）来鉴定该系列化合物并优化其结构及相关活性关系。二甲胺类似物LY333531（1），即（S）-13-[(二甲氨基)甲基]-10,11,14,15-四氢-4,9:16,21-二亚甲基-1H,13H-二苯并[e,k]吡咯并[3,4-h][1,4,13]恶二氮杂环十六碳烯-1,3(2H)-二酮，可抑制PKCβI（IC50 = 4.7 nM）和PKCβII（IC50 = 5.9 nM）同工酶，与PKCα相比，对PKCβI和PKCβII抑制的选择性分别为76倍和61倍。该系列中描述的其他类似物也是PKCβ的选择性抑制剂。LY333531（1）对PKCβI表现出ATP依赖性竞争性抑制，与其他ATP依赖性激酶（蛋白激酶A、钙调蛋白、酪蛋白激酶、src酪氨酸激酶）相比，对PKC具有选择性。使用牛视网膜毛细血管内皮细胞评估了该系列化合物的细胞活性。视网膜内皮细胞功能障碍与糖尿病视网膜病变的发生有关。该系列化合物可抑制佛波酯（4β-佛波醇12,13-二丁酸酯）刺激的内皮细胞中的纤溶酶原激活物活性，ED50值范围为7.5至0.21 microM。提供了该系列化合物的PKC同工酶和相关ATP依赖性激酶抑制谱，并与非选择性PKC抑制剂星形孢菌素的谱进行了比较。将该系列化合物的细胞活性与激酶抑制剂星形孢菌素的细胞活性进行了比较。
