Optimization of small molecule agonists of the thrombopoietin (Tpo) receptor derived from a benzo[a]carbazole hit scaffold

  • Bioorg Med Chem Lett. 2008 Oct 1;18(19):5259-62. doi: 10.1016/j.bmcl.2008.08.077.
Thomas H Marsilje  1 ,  Phil B Alper ,  Wenshuo Lu ,  Daniel Mutnick ,  Pierre-Yves Michellys ,  Yun He ,  Donald S Karanewsky ,  Donald Chow ,  Andrea Gerken ,  Jianmin Lao ,  Min-Ju Kim ,  H Martin Seidel ,  Shin-Shay Tian
Affiliations
  • 1. Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA 92121, USA. [email protected]
PMID: 18783949 DOI: 10.1016/j.bmcl.2008.08.077
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.