Department of Chemistry, Center for Molecular Innovation and Drug Discovery, and Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
J Med Chem. 2010 Nov 11;53(21):7804-24. doi: 10.1021/jm100947x.
Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure-activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((±)-32 and (±)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2''-(3'''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437 - 5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.
神经元型一氧化氮合酶 (nNOS) 是预防脑损伤和治疗各种神经退行性疾病的重要治疗靶点。设计并合成了一系列反式取代的氨基吡咯烷甲基 2-氨基吡啶衍生物（8-34）。通过构效关系分析，发现了低纳摩尔浓度的 nNOS 抑制剂 ((±)-32 和 (±)-34)，其对 nNOS 的选择性超过 eNOS 达 1000 倍以上。还合成了四个对映异构体纯的 3'-[2''-(3'''-氟苯乙氨基)乙氧基]吡咯烷-4'-基}甲基}-4-甲基吡啶-2-胺（4）。结果发现，(3'R,4'R)-4 可以诱导酶的弹性，从而产生新的配体结合“热点”。抑制剂采用独特的结合模式，与 3'-[2''-(3'''-氟苯乙氨基)乙基氨基]吡咯烷-4'-基}甲基}-4-甲基吡啶-2-胺 ((3'R,4'R)-3)（J. Am. Chem. Soc. 2010, 132 (15), 5437 - 5442）观察到的相同。基于 8-34 的构效关系和 3 和 4 的顺式和反式异构体的不同结合构象，揭示了 NOS 活性位点对配体结合的关键结构要求。
