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

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Marsilje TH, Alper PB, Lu W, Mutnick D, Michellys PY, He Y, Karanewsky DS, Chow D, Gerken A, Lao J, Kim MJ, Seidel HM, Tian SS

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. Epub 2008 Aug 26.

PubMed ID

18783949 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Eltrombopag	Thrombopoietin receptor	EC 50 (nM)	38	N/A	N/A	Details