Balani S K, Goldman M E, Kauffman L R, Varga S L, O'Brien J A, Smith S J, Olah T V, Ramjit H G, Schorn T W, Pitzenberger S M
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486.
Drug Metab Dispos. 1993 Jul-Aug;21(4):598-604.
Rhesus monkeys were dosed orally with 10 mg/kg 5-chloro-3-phenylthioindole-2-carboxamide (L-734,005), a nonnucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, in polyethylene glycol 300. Plasma samples from these monkeys demonstrated greater bioactivity in an HIV-1 reverse transcriptase inhibition assay than anticipated from the parent compound concentrations as determined by an HPLC-UV assay. One major and three minor metabolites, as well as the parent compound, were detected in the plasma. One of the minor metabolites was determined to be several-fold more active, and the major metabolite one-half as active as the parent compound in the inhibition assay. Identical metabolites were formed during an incubation of L-734,005 with rat liver microsomes. The most active minor metabolite was identified as a sulfone analog (L-737,126) of the parent compound by NMR and MS analyses. The less active major metabolite and two relatively inactive minor metabolites were similarly identified as the sulfoxide, 4-hydroxythiophenyl and 6-hydroxyindole analogs of L-734,005. The synthetic sulfone analog was highly potent against HIV-1, with a 95% inhibitory concentration of 3.0 nM for the spread of virus infection in a cell culture.
将10毫克/千克的5-氯-3-苯硫基吲哚-2-甲酰胺（L-734,005，一种非核苷类人类免疫缺陷病毒1型（HIV-1）逆转录酶抑制剂）溶于聚乙二醇300中，对恒河猴进行口服给药。在HIV-1逆转录酶抑制试验中，这些猴子的血浆样本所显示出的生物活性高于通过高效液相色谱-紫外检测法测定的母体化合物浓度所预期的活性。在血浆中检测到一种主要代谢物、三种次要代谢物以及母体化合物。在抑制试验中，其中一种次要代谢物的活性被测定为母体化合物的几倍，而主要代谢物的活性为母体化合物的一半。在L-734,005与大鼠肝微粒体的孵育过程中形成了相同的代谢物。通过核磁共振（NMR）和质谱（MS）分析，活性最高的次要代谢物被鉴定为母体化合物的砜类似物（L-737,126）。活性较低的主要代谢物和两种相对无活性的次要代谢物同样被鉴定为L-734,005的亚砜、4-羟基硫苯基和6-羟基吲哚类似物。合成的砜类似物对HIV-1具有高度活性，在细胞培养中对病毒感染传播的95%抑制浓度为3.0纳摩尔。
