Optimization of alkylidene hydrazide based human glucagon receptor antagonists.: Discovery of the highly potent and orally available 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide
Optimization of alkylidene hydrazide based human glucagon receptor antagonists.: Discovery of the highly potent and orally available 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide
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DOI：
10.1021/jm0208572
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发表时间：
2002-12-19
影响因子：
7.3
通讯作者：
Lau, J
中科院分区：
文献类型：
--
作者：
Madsen, P;Ling, A;Lau, J
高效的人胰高血糖素受体（hGluR）拮抗剂已经采用药物化学和靶向文库制备，所述靶向文库基于对2，3-氰基-4-羟基苯甲酸（3，5-二甲氧基-4-异丙基苄氧基苄亚甲基）酰肼先导物的核心（近端）二甲氧基苯基、苄基醚键以及（远端）苄基芳基的修饰。富含电子的近端芳基部分，如单-和二甲氧基苯，萘，和吲哚被发现是活跃的。SAR被认为是非常不敏感的关于连接到远端芳基，因为长和短以及极性和非极性的连接子得到高度有效的化合物。远端芳基的存在对于获得对hGluR的高结合亲和力不是至关重要的。然而，在许多情况下，可以用取代的远端芳基进一步优化亲和力。代表性的化合物已在体外代谢进行了测试，并描述了结构-代谢关系。这些努力导致发现了74，NNC 25-2504，3-氰基-4-羟基苯甲酸[1-（2，3，5，6-四甲基苄基）-1H-吲哚-4-基亚甲基酰肼，体外代谢转换率低。74是人胰高血糖素受体（IC 50 = 2.3 nM，K-B = 760 pM）和分离的大鼠受体（IC 50 = 430 pM，K-B = 380 pM）的高效非竞争性拮抗剂。胰高血糖素刺激的葡萄糖生产从分离的原代大鼠肝细胞被竞争性抑制74（Ki = 14 nM）。该化合物可在犬中口服（F-po = 15%），并在高胰高血糖素血症和高血糖症的胰高血糖素激发大鼠模型中具有活性。
Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-eyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylenelhydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC50 = 2.3 nM, K-B = 760 pM) and of the isolated rat receptor IC50 = 430 pM, K-B = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K-i = 14 nM). This compound was orally available in dogs (F-po = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.