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Issue 38, 2017
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On the discovery of new potent human farnesyltransferase inhibitors: emerging pyroglutamic derivatives

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Abstract

In the current context of lack of emergence of innovative human farnesyltransferase inhibitors families, and given all new therapeutic perspectives that open up for such molecules in rare diseases (e.g. Hutchinson–Gilford progeria syndrome), and in delta hepatitis, cardiovascular or neuroinflammatory diseases, we have just discovered a new series of powerful inhibitors. These molecules are pyroglutamic acid derivatives, and were evaluated on human farnesyltransferase in vitro then modeled in silico on the active site of the protein. Three main points of the pyroglutamic acid cycle have undergone chemical modulations pyroglutamides in position 5 (compounds 7a–h), constrained bicyclic analogues of pyrroloimidazoledione type (compounds 1a–h), modulation of the position 3 (compounds 2–5 and 8), and allowed the first SAR in the field. Five derivatives in the current work have IC50 values in the small nanomolar range (2–5 nM). These new lead compounds open the way for the next generation of farnesyltransferase inhibitors.

Graphical abstract: On the discovery of new potent human farnesyltransferase inhibitors: emerging pyroglutamic derivatives

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Publication details

The article was received on 20 Jun 2017, accepted on 08 Sep 2017 and first published on 08 Sep 2017


Article type: Paper
DOI: 10.1039/C7OB01489A
Citation: Org. Biomol. Chem., 2017,15, 8110-8118
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    On the discovery of new potent human farnesyltransferase inhibitors: emerging pyroglutamic derivatives

    G. Homerin, E. Lipka, B. Rigo, A. Farce, J. Dubois and A. Ghinet, Org. Biomol. Chem., 2017, 15, 8110
    DOI: 10.1039/C7OB01489A

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