Farnesyl pyrophosphate synthase enantiospecificity with a chiral risedronate analog, [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501): Synthetic, structural, and modeling studies.

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Deprele S, Kashemirov BA, Hogan JM, Ebetino FH, Barnett BL, Evdokimov A, McKenna CE

Bioorg Med Chem Lett. 2008 May 1;18(9):2878-82. doi: 10.1016/j.bmcl.2008.03.088. Epub 2008 Apr 8.

PubMed ID

18434151 [ View in PubMed

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Abstract

The complex formed from crystallization of human farnesyl pyrophosphate synthase (hFPPS) from a solution of racemic [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501, 8), a chiral analog of the anti-osteoporotic drug risedronate, contained the R enantiomer in the enzyme active site. This enantiospecificity was assessed by computer modeling of inhibitor-active site interactions using Autodock 3, which was also evaluated for predictive ability in calculations of the known configurations of risedronate, zoledronate, and minodronate complexed in the active site of hFPPS. In comparison with these structures, the 8 complex exhibited certain differences, including the presence of only one Mg(2+), which could contribute to its 100-fold higher IC(50). An improved synthesis of 8 is described, which decreases the number of steps from 12 to 8 and increases the overall yield by 17-fold.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Risedronic acid	Farnesyl pyrophosphate synthase	IC 50 (nM)	5.7	N/A	N/A	Details