Hagen T J, Bergmanis A A, Kramer S W, Fok K F, Schmelzer A E, Pitzele B S, Swenton L, Jerome G M, Kornmeier C M, Moore W M, Branson L F, Connor J R, Manning P T, Currie M G, Hallinan E A
Discovery Medicinal Chemistry, Searle, Monsanto, 4901 Searle Parkway, Skokie, Illinois 60077, Discovery Pharmacology, Searle, Monsanto, 800 North Lindbergh Boulevard, St. Louis, Missouri 63167, USA.
J Med Chem. 1998 Sep 10;41(19):3675-83. doi: 10.1021/jm970840x.
A series of substituted 2-iminopyrrolidines has been prepared and shown to be potent and selective inhibitors of the human inducible nitric oxide synthase (hiNOS) isoform versus the human endothelial nitric oxide synthase (heNOS) and the human neuronal nitric oxide synthase (hnNOS). Simple substitutions at the 3-, 4-, or 5-position afforded more potent analogues than the parent 2-iminopyrrolidine 1. The effect of ring substitutions on both potency and selectivity for the different NOS isoforms is described. Substitution at the 4- and 5-positions of the 2-iminopyrrolidine yielded both potent and selective inhibitors of hiNOS. In particular, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine, monohydrochloride (20), displayed potent inhibition of hiNOS (IC50 = 0.25 microM) and selectivities of 897 (heNOS IC50/hiNOS IC50) and 13 (hnNOS IC50/hiNOS IC50). Example 20 was shown to be an efficacious inhibitor of NO production in the mouse endotoxin assay. Furthermore, 20 displayed in vivo selectivity, versus heNOS isoform, by not elevating blood pressure at multiples of the effective dose in the mouse.
一系列取代的2-亚氨基吡咯烷已被制备出来，并显示出对人诱导型一氧化氮合酶（hiNOS）亚型具有强效和选择性抑制作用，相对于人内皮型一氧化氮合酶（heNOS）和人神经元型一氧化氮合酶（hnNOS）。在3、4或5位进行简单取代得到的类似物比母体2-亚氨基吡咯烷1更具活性。描述了环取代对不同NOS亚型的活性和选择性的影响。在2-亚氨基吡咯烷的4位和5位进行取代产生了hiNOS的强效和选择性抑制剂。特别地，（+）-顺式-4-甲基-5-戊基吡咯烷-2-亚胺单盐酸盐（20）对hiNOS表现出强效抑制作用（IC50 = 0.25 microM），对heNOS的选择性为897（heNOS IC50/hiNOS IC50），对hnNOS的选择性为13（hnNOS IC50/hiNOS IC50）。在小鼠内毒素试验中，化合物20被证明是NO产生的有效抑制剂。此外，在小鼠中，以有效剂量的倍数给药时，20对heNOS亚型显示出体内选择性，即不会升高血压。
