Author/Authors :
Thomas H. Marsilje، نويسنده , , Phil B. Alper، نويسنده , , Wenshuo Lu، نويسنده , , Daniel Mutnick، نويسنده , , Pierre-Yves Michellys، نويسنده , , Yun He، نويسنده , , Donald S. Karanewsky، نويسنده , , Donald Chow، نويسنده , , Andrea Gerken، نويسنده , , Jianmin Lao، نويسنده , , Minju Kim، نويسنده , , H. Martin Seidel، نويسنده , , Shin-Shay Tian، نويسنده ,
Abstract :
The lead optimization of a novel series of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. The chemical instability of the dihydro-benzo[a]carbazole lead 2 was successfully addressed in the design and evaluation of compounds which also demonstrated improved potency compared to 2. Members of the scaffold have been identified which are full agonists that demonstrate cellular functional potency <50 nM. Analog 21 demonstrates equivalent efficacy in the human megakaryocyte differentiation (CFU-mega) assay compared to Eltrombopag™.
Keywords :
TPO , Thrombopoietin , TPOR , cMpl , Hematopoietic growth factor , agonist
