Kerr J S, Batt D G, Pinto D J, Stampfli H F
Du Pont Merck Pharmaceutical Company, Inflammatory Diseases Research, Wilmington, DE 19898.
Res Commun Chem Pathol Pharmacol. 1992 Jul;77(1):77-86.
DuP 654 (2-benzyl-1-naphthol) is a topically active anti-inflammatory agent that was evaluated in phase II clinical trials as an anti-psoriatic agent. The compound is a potent 5-lipoxygenase inhibitor and exhibits inhibitory activity against lipopolysaccharide-stimulated release of interleukin-1 from human monocytes. DuP 654 cannot be used as a systemic anti-inflammatory compound due to its rapid and extensive metabolism. Fifteen analogs were synthesized in an attempt to block the systemic route(s) of metabolism. The compounds were evaluated (IP and PO) in the rat carrageenan paw edema inflammation model with plasma samples taken at 1, 2, 3, and 4 hours post-dose. Substitutions at the 4- and/or 8-positions on the naphthol, and/or on the benzyl group of the DuP 654 molecule were unsuccessful in achieving an analog which displayed both oral activity in the inflammatory model and high plasma levels without manifesting toxicity. The low plasma levels of some analogs may indicate poor absorption, high volume of distribution, or that the substitution did not inhibit the high hepatic "first-pass" metabolism observed with DuP 654. Other compounds not studied but similar in structure to DuP 654 may exhibit rapid and extensive metabolism.
DuP 654（2-苄基-1-萘酚）是一种局部活性抗炎剂，曾作为抗银屑病药物进行II期临床试验。该化合物是一种有效的5-脂氧合酶抑制剂，对脂多糖刺激人单核细胞释放白细胞介素-1具有抑制活性。由于其快速且广泛的代谢，DuP 654不能用作全身性抗炎化合物。合成了15种类似物，试图阻断其全身代谢途径。在大鼠角叉菜胶足爪水肿炎症模型中对这些化合物进行了评价（腹腔注射和口服），并在给药后1、2、3和4小时采集血浆样本。在DuP 654分子的萘酚4位和/或8位以及/或者苄基上进行取代，未能成功得到一种在炎症模型中具有口服活性且血浆水平高而无毒性表现的类似物。一些类似物体内血浆水平低可能表明吸收差、分布容积大，或者该取代未能抑制DuP 654所观察到的肝脏高“首过”代谢。其他未研究但结构与DuP 654相似的化合物可能也表现出快速且广泛的代谢。
