Ohemeng K A, Appollina M A, Nguyen V N, Schwender C F, Singer M, Steber M, Ansell J, Argentieri D, Hageman W
R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869.
J Med Chem. 1994 Oct 14;37(21):3663-7. doi: 10.1021/jm00047a023.
A series of 2-substituted benzofuran hydroxyamic acids were synthesized as rigid analogs of simple (benzyloxy)phenyl hydroxamates, evaluated for their in vitro and in vivo 5-lipoxygenase activity and found to be potent inhibitors of the enzyme. Substituents which enhanced lipophilicity near the 2-position of the benzofuran nucleus increased inhibitor potency but reduced oral activity. Incorporation of small polar substituents such as methoxymethylene, hydroxymethylene, and amino (urea) on the acyl group led to more consistent oral activity. The most potent inhibitors of this series in vitro were N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)-ethyl]furancarboxamide (12) and methyl 5-[N-hydroxy-N-[1-(2-(3,4,5-trimethoxyphenyl)-5-benzofuranyl]ethyl]-5- oxopentanoate (17), both with IC50 values of 40 nM, and in vivo the most potent compound was N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea, 20, with an ED50 = 10.3 mg/kg.
合成了一系列2-取代苯并呋喃异羟肟酸作为简单（苄氧基）苯基异羟肟酸的刚性类似物，对其体外和体内5-脂氧合酶活性进行了评估，发现它们是该酶的有效抑制剂。在苯并呋喃核的2-位附近增强亲脂性的取代基增加了抑制剂的效力，但降低了口服活性。在酰基上引入小的极性取代基，如甲氧基亚甲基、羟基亚甲基和氨基（脲），导致口服活性更一致。该系列中体外最有效的抑制剂是N-羟基-N-[1-(2-苯基-5-苯并呋喃基)乙基]呋喃甲酰胺（12）和5-[N-羟基-N-[1-(2-(3,4,5-三甲氧基苯基)-5-苯并呋喃基]乙基]-5-氧代戊酸甲酯（17），两者的IC50值均为40 nM，而体内最有效的化合物是N-羟基-N-[1-(2-苯基-5-苯并呋喃基)乙基]脲（20），ED50 = 10.3 mg/kg。
