Structure-based optimization of novel azepane derivatives as PKB inhibitors
Structure-based optimization of novel azepane derivatives as PKB inhibitors
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DOI：
10.1021/jm0310479
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发表时间：
2004-03-11
影响因子：
7.3
通讯作者：
Masjost, B
中科院分区：
文献类型：
--
作者：
Breitenlechner, CB;Wegge, T;Masjost, B
制备新型氮杂环庚烷衍生物并评价其对蛋白激酶B（PKB-α）和蛋白激酶A（PKA）的抑制作用。原始的（-）-balanol衍生的先导结构（4 R）-4-（2氟-6-羟基-3-甲氧基-苯甲酰基）-苯甲酸（3R）-3-[（吡啶-4-羰基）氨基]-氮杂环庚烷4-基酯（1）（IC 50（PKB-α.）= 5 nM），其含有酯部分，被发现是血浆不稳定的，因此不适合作为药物。基于使用PKA和1之间的复合物的晶体结构的分子模拟研究，五种化合物N-{（3R，4 R）-4-[4-（4-氨基苯基）-2-甲基-N-（2-氨基苯基）-3-甲基-N-（3-氨基苯基）-2-甲基-（3-氨基苯基）-2-甲基（2-氟-6-羟基-3-甲氧基-苯甲酰基）-苯甲酰基氨基]-氮杂环庚烷-3-基}-异烟酰胺（4），（2-氟-6-羟基-3-甲氧基-苯甲酰基）-苄氧基]-氮杂环庚烷-3-基}-异烟酰胺（5），（2-氟-6-羟基-3-甲氧基-苯甲酰基）-苯基氨基]-甲基}-氮杂环庚烷-3-基）-异烟酰胺（6），（2-氟-6-羟基-3-甲氧基-苯甲酰基）-苄基氨基]-氮杂环庚烷-3-基}-异烟酰胺（7），和N-{（3R，4S）-4-设计、合成了（4-{反式-2-[4-（2-氟-6-羟基-3-甲氧基-苯甲酰基）-苯基] -乙烯基}-氮杂环庚烷-3-基）-异烟酰胺（8），并测试对PKA和PKB-α的体外抑制活性以及在小鼠血浆中的血浆稳定性。（1）发现化合物4是血浆稳定的和高活性的（IC 50（PKB-α）= 4 nM）。获得了4、5和8的具有PKA的共晶体，并分析了配体和蛋白质中的结合相互作用和构象变化，以使分子的不同活性合理化。
Novel azepane derivatives were prepared and evaluated for protein kinase B (PKB-alpha) and protein kinase A (PKA) inhibition. The original (-)-balanol-derived lead structure (4R)-4-(2fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R)-3-[(pyridine-4-carbonyl)aminol-azepan4-yl ester (1) (IC50 (PKB-alpha.) = 5 nM) which contains an ester moiety was found to be plasma unstable and therefore unsuitable as a drug. Based upon molecular modeling studies using the crystal structure of the complex between PKA and 1, the five compounds N-{(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]-azepan-3-yl}-isonicotinamide (4), (3R,4R)-N-{4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzyloxy]-azepan-3-yl}-isonicotinamide (5), N-{(3R,4S)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenylamino]-methyl}-azepan-3-yl)-isonicotinamide (6), N-{(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzylamino]-azepan-3-yl}-isonicotinamide (7), and N-{(3R,4S)-4-(4-{trans-2-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenyl] -vinyl}-azepan-3-yl)-isonicotinamide (8) with linkers isosteric to the ester were designed, synthesized, and tested for in vitro inhibitory activity against PKA and PKB-alpha and for plasma stability in mouse plasma.(1)Compound 4 was found to be plasma stable and highly active (IC50 (PKB-alpha) = 4 nM). Cocrystals with PKA were obtained for 4, 5, and 8 and analyzed for binding interactions and conformational changes in the ligands and protein in order to rationalize the different activities of the molecules.