Elkihel L, Loiseau P M, Bourass J, Gayral P, Letourneux Y
Laboratoire de Génie Protéique, Physicochimie des Substances Naturelles, Université de La Rochelle, France.
Arzneimittelforschung. 1994 Nov;44(11):1259-64.
The development of new macrofilaricidal drugs is described following a strategy for the promotion of the lymphatic transport of anthelminthic drugs by-passing the liver. The selected compound was niclosamide (CAS 50-65-7) which is very effective in vitro against infective larvae but has no significant antifilarial activity when orally administered at 200 mumol/kg. To estimate the interest of such an approach, the synthesis of 5 prodrugs was achieved in a first stage. The intrinsic antifilarial activity and the delayed effect of these compounds were evaluated in vitro. Then, in vivo tests were performed with Molinema dessetae infective larvae to select the best ligands. The prodrug V 1,3-dihexadecanamido-2-[4-chloro(2- chloro-4-nitroanilinocarbonyl)phenyloxy-carbonylpropanoyl oxy]propane (having a diamide function) was responsible for an in vitro delayed effect and an orally in vivo activity (200 mumol/kg when administered in a single dose). The biological improvement of this easily micellizable prodrug which is stable to intestinal enzymes in respect to Niclosamide confirms such a strategy.
本文描述了新型杀丝虫药物的研发过程，该研发遵循一种策略，即通过绕过肝脏来促进驱虫药物的淋巴转运。所选化合物为氯硝柳胺（CAS 50-65-7），其在体外对感染性幼虫非常有效，但以200 μmol/kg口服给药时，抗丝虫活性不显著。为评估这种方法的可行性，第一阶段合成了5种前药。对这些化合物的内在抗丝虫活性和延迟效应进行了体外评估。然后，用德氏莫尼线虫感染性幼虫进行体内试验，以筛选出最佳配体。前药V 1,3-二十六烷二酰胺基-2-[4-氯（2-氯-4-硝基苯胺羰基）苯氧基羰基丙酰氧基]丙烷（具有二酰胺功能）具有体外延迟效应和口服体内活性（单次给药200 μmol/kg）。与氯硝柳胺相比，这种易于形成胶束且对肠道酶稳定的前药在生物学性能上的改善证实了这一策略。
