Ralf Haiges - Synthesis, stereochemistry and SAR of a series of minodronate analogues as RGGT inhibitors.

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      Publication Details (including relevant citation   information): Blazewska, Katarzyna M., Ni, Feng, Haiges,   Ralf, Kashemirov, Boris A., Coxon, Fraser P., Stewart, Charlotte   A., Baron, Rudi, Rogers, Michael J., Seabra, Miguel C., Ebetino,   Frank H., McKenna, Charles E., Eur. J. Med. Chem.,   2011, 46 (10), pp 4820-4826

      Abstract: Phosphonocarboxylate (PC) analogs of   bisphosphonates are of interest due to their selective inhibition   of a key enzyme in the mevalonate pathway, Rab geranylgeranyl   transferase (RGGT). The dextrorotatory enantiomer of   2-hydroxy-3-(imidazo[1,2-a]pyridin-3-yl)-2-phosphonopropanoic   acid (3-IPEHPC, 1) is the most potent PC-type RGGT inhibitor thus   far identified. The abs. configuration of (+)-1 in the active   site complex has remained unknown due to difficulties in   obtaining RGGT inhibitor complex crystals suitable for x-ray   diffraction anal. However, authors have now succeeded in crystg.   (-)-1 and here report its abs. configuration (AC) obtained by   x-ray crystallog., thus also defining the AC of (+)-1. An   Autodock Vina 1.1 computer modeling study of (+)-1 in the active   site of modified RGGT binding GGPP (3DSV) identifies   stereochem.-dependent interactions that could account for the   potency of (+)-1 and supports the hypothesis that this type of   inhibitor binds at the TAG tunnel, inhibiting the second   geranylgeranylation step. It is also reported a convenient 31P   NMR method to det. enantiomeric excess of 1 and its pyridyl   analog 2, using α- and β-cyclodextrins as chiral solvating   agents, and describe the synthesis of a small series of 1 α-X (X   = H, F, Cl, Br; 7a-d) analogs to assess the contribution of the   α-OH group to activity at enzyme and cellular levels. The IC50 of   1 was 5-10× lower than 7a-d, and the LED for inhibition of Rab11   prenylation in vitro was 2-8× lower than for 7a-d. However, in a   viability redn. assay with J774 cells, 1 and 7b had similar IC50   values, ∼10× lower than those of 7a and 7c-d. [on SciFinder(R)]

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