The discovery of potent, selective CCR2 antagonists at BMS began with an acyclic dianimopropionamide-glycine dipeptide series, hypothesized to from intramolecular hydrogen bonds, stabilizing the bound conformation. This hypothesis led to the design of cyclic scaffolds, resulting in a set of disubstituted piperidines and ultimately trisubstituted cyclohexanes. While it was predicted that the three chemotypes bound in a similar manner, mutagenesis data suggested some variation in the specific receptor-ligand contacts. In addtion to the closely related series above, an additional unrelated caroboxylic acid bearing chemotype was discovered via screening. As a means to understand SAR, bioactive conformation and mutagenesis data, structural models were constructed based on homologous receptors.<br/><br/>Recently, a crystal structure of CCR2 in complex with a BMS trisubstituted cyclohexyl analog, BMS-687681 and an allosteric modulator was reported providing key insights into receptor conformation and the small molecule binding modes, particularly the acid bearing chemotypes which bind into a previously unidentified allosteric site.<br/>During the course of this presentation, the predictions from the original homology models and comparison of these models to the experimental structures will be discussed. In addition, the SAR and mutagenesis will be revisited in the three dimensional context of the crystal structure.

Use of modeling and crystallography to understand CCR2 antagonist SAR and receptor binding

255th National Meeting (2018)

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