Madsen Peter, Ling Anthony, Plewe Michael, Sams Christian K, Knudsen Lotte B, Sidelmann Ulla G, Ynddal Lars, Brand Christian L, Andersen Birgitte, Murphy Douglas, Teng Min, Truesdale Larry, Kiel Dan, May John, Kuki Atsuo, Shi Shenghua, Johnson Michael D, Teston Kimberly Ann, Feng Jun, Lakis James, Anderes Kenna, Gregor Vlad, Lau Jesper
Department of Medicinal Chemistry, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
J Med Chem. 2002 Dec 19;45(26):5755-75. doi: 10.1021/jm0208572.
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-cyano-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-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC(50) = 2.3 nM, K(B) = 760 pM) and of the isolated rat receptor (IC(50) = 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.
基于先导化合物2,3-氰基-4-羟基苯甲酸(3,5-二甲氧基-4-异丙基苄氧基亚苄基)酰肼的核心（近端）二甲氧基苯基、苄基醚键以及（远端）苄基芳基的修饰，利用药物化学和靶向文库制备了高效的人胰高血糖素受体（hGluR）拮抗剂。发现富电子的近端芳基部分如单甲氧基苯、二甲氧基苯、萘和吲哚具有活性。发现构效关系对与远端芳基的连接相当不敏感，因为长链和短链以及极性和非极性连接基都能产生高效的化合物。远端芳基的存在对于获得与hGluR的高结合亲和力并非至关重要。然而，在许多情况下，用取代的远端芳基可以进一步优化亲和力。已对代表性化合物进行了体外代谢测试，并描述了结构-代谢关系。这些研究工作导致发现了74（NNC 25-2504），即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，其体外代谢周转率较低。74是一种高效的人胰高血糖素受体非竞争性拮抗剂（IC(50) = 2.3 nM，K(B) = 760 pM）以及分离的大鼠受体拮抗剂（IC(50) = 430 pM，K(B) = 380 pM）。74可竞争性抑制分离的原代大鼠肝细胞中胰高血糖素刺激的葡萄糖生成（K(i) = 14 nM）。该化合物在犬体内具有口服生物利用度（F(po) = 15%），并且在胰高血糖素激发的高胰高血糖素血症和高血糖大鼠模型中具有活性。
