Structure-Activity Relation SAR of Ecdysteroids

The SAR of the bisacylhydrazines, both during and after the discovery of the commercial compounds, has been extensively studied. This was partly driven by the novelty of the chemistry, mode of action (ecdysone agonists via interaction with the ecdysone receptor), and the availability of suitable assays (tissue, cell and target site based). Numerous papers have been published on this subject and the reader is referred to an excellent review by Dinan and Hormann [6] as a starting point. This section highlights and summarizes the collective findings by various researchers. 

In considering the SAR of bisacylhydrazines for the discovery of new and novel ecdysone agonists, it is essential to understand the SAR of ecdysteroids. This helps to define the three-dimensional (3D) space of ecdysteroids in the EcR LBD and allows for overlaps and comparison with BAH or other ecdysone agonist chemotypes (described below). 

Publication of the crystal structure of the Hdiothis viresence EcR (HvEcR) LBD heterodimerized with LBD of H. viresence ultraspiracle protein (HvUSP) with and without ponasterone A (phytoecdysteroid) or a BAH ecdysone agonist provided a more realistic conformation of the HvEcR LBD and the ligands in the LBD [21]. The most surprising result was that ponasterone A co-crystallized in the HvEcR LBD in an orientation opposite to that predicted by the CoMEA, 4D-QSAR and 

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