Hansen D W, Peterson K B, Trivedi M, Kramer S W, Webber R K, Tjoeng F S, Moore W M, Jerome G M, Kornmeier C M, Manning P T, Connor J R, Misko T P, Currie M G, Pitzele B S
Department of Discovery Medicinal Chemistry, G. D. Searle Research and Development, 4901 Searle Parkway, Skokie, Illinois 60077, USA.
J Med Chem. 1998 Apr 23;41(9):1361-6. doi: 10.1021/jm9704715.
An attractive approach to the treatment of inflammatory conditions such as osteo- and rheumatoid arthritis, inflammatory bowel disease, and sepsis is through the selective inhibition of human inducible nitric oxide synthase (hiNOS) since localized excess nitric oxide (NO) release has been implicated in the pathology of these diseases. A series of monosubstituted iminohomopiperidinium salts possessing lipophilic functionality at ring positions 3, 5, 6, and 7 has been synthesized, and series members have demonstrated the ability to inhibit the hiNOS isoform with an IC50 as low as 160 nM (7). Compounds were found that selectively inhibit hiNOS over the human endothelial constitutive enzyme (heNOS) with a heNOS/hiNOS IC50 ratio in excess of 100 and as high as 314 (9). Potencies for inhibition of hiNOS and the human neuronal constitutive enzyme (hnNOS) are comparable. Substitution in the 3 and 7 positions provides compounds that exhibit the greatest degree of selectivity for hiNOS and hnNOS over heNOS. Submicromolar potencies for 6 and 7 in a mouse RAW cell assay demonstrated the ability of these compounds to inhibit iNOS in a cellular environment. These latter compounds were also found to be orally bioavailable and efficacious due to their ability to inhibit the increase in plasma nitrite/nitrate levels in a rat LPS model.
一种治疗诸如骨关节炎和类风湿性关节炎、炎症性肠病以及败血症等炎症性疾病的有效方法是通过选择性抑制人诱导型一氧化氮合酶（hiNOS），因为局部过量释放一氧化氮（NO）与这些疾病的病理过程有关。已合成了一系列在环位置3、5、6和7处具有亲脂性功能的单取代亚氨基高哌啶盐，并且系列成员已证明具有抑制hiNOS亚型的能力，其IC50低至160 nM（7）。发现化合物对人内皮组成型酶（heNOS）具有选择性抑制hiNOS的作用，heNOS/hiNOS的IC50比值超过100，高达314（9）。抑制hiNOS和人神经元组成型酶（hnNOS）的效力相当。在3和7位进行取代可提供对hiNOS和hnNOS相对于heNOS表现出最大程度选择性的化合物。在小鼠RAW细胞试验中，6位和7位化合物的亚微摩尔效力证明了这些化合物在细胞环境中抑制诱导型一氧化氮合酶（iNOS）的能力。还发现这些后一种化合物具有口服生物利用度且有效，因为它们能够在大鼠脂多糖模型中抑制血浆亚硝酸盐/硝酸盐水平的升高。
