Becknell Nadine C, Zulli Allison L, Angeles Thelma S, Yang Shi, Albom Mark S, Aimone Lisa D, Robinson Candy, Chang Hong, Hudkins Robert L
Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
Bioorg Med Chem Lett. 2006 Oct 15;16(20):5368-72. doi: 10.1016/j.bmcl.2006.07.066. Epub 2006 Aug 4.
A novel series of C-3 urea, amide, and carbamate fused dihydroindazolocarbazole (DHI) analogs are reported as highly potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases with excellent cellular potency. Structure-activity relationship (SAR) studies indicate the optimal N-13 alkyl substitutions are n-propyl and i-butyl. The isopropyl carbamate 39 displayed good dual enzyme, cell potency, and rat pharmacokinetic properties for advancement to in vivo evaluation.
据报道，一系列新型的C-3尿素、酰胺和氨基甲酸酯稠合二氢吲哚并咔唑（DHI）类似物是TIE-2和VEGF-R2受体酪氨酸激酶的高效双重抑制剂，具有出色的细胞活性。构效关系（SAR）研究表明，最佳的N-13烷基取代基是正丙基和异丁基。异丙基氨基甲酸酯39表现出良好的双重酶活性、细胞活性和大鼠药代动力学性质，可推进至体内评估。
