Optimization of small molecule agonists of the thrombopoietin (Tpo) receptor derived from a benzo[a]carbazole hit scaffold |
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Authors: | Marsilje Thomas H Alper Phil B Lu Wenshuo Mutnick Daniel Michellys Pierre-Yves He Yun Karanewsky Donald S Chow Donald Gerken Andrea Lao Jianmin Kim Min-Ju Seidel H Martin Tian Shin-Shay |
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Affiliation: | Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA 92121, USA. TMarsilje@gnf.org |
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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. |
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