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

Sylvine Deprèle; Boris A Kashemirov; James M Hogan; Frank H Ebetino; Bobby L Barnett; Artem Evdokimov; Charles E McKenna

doi:10.1016/j.bmcl.2008.03.088

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

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

Authors

Sylvine Deprèle¹, Boris A Kashemirov, James M Hogan, Frank H Ebetino, Bobby L Barnett, Artem Evdokimov, Charles E McKenna

Affiliation

¹ Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA.

PMID: 18434151
DOI: 10.1016/j.bmcl.2008.03.088

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Algorithms
Binding Sites
Bone Density Conservation Agents / chemical synthesis
Bone Density Conservation Agents / pharmacology*
Carcinoma / drug therapy
Carcinoma / enzymology
Computer Simulation*
Crystallography, X-Ray
Diphosphonates / chemistry
Diphosphonates / pharmacology
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
Etidronic Acid / analogs & derivatives*
Etidronic Acid / chemistry
Etidronic Acid / pharmacology
Farnesyltranstransferase / antagonists & inhibitors*
Humans
Imidazoles / chemistry
Imidazoles / pharmacology
Inhibitory Concentration 50
Magnesium / chemistry
Magnesium / metabolism
Models, Chemical
Organophosphonates / chemical synthesis
Organophosphonates / pharmacology*
Pyridines / chemical synthesis
Pyridines / pharmacology*
Risedronic Acid
Stereoisomerism
Structure-Activity Relationship
Zoledronic Acid

Substances

(6,7-dihydro-5H-cyclopenta(c)pyridin-7-yl(hydroxy)methylene)bis(phosphonic acid)
Bone Density Conservation Agents
Diphosphonates
Enzyme Inhibitors
Imidazoles
Organophosphonates
Pyridines
YM 529
Zoledronic Acid
Farnesyltranstransferase
Magnesium
Risedronic Acid
Etidronic Acid