Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption

John M. Sanders; Yongcheng Song; Julian M.W. Chan; Yonghui Zhang; Samuel Jennings; Thomas Kosztowski; Sarah Odeh; Ryan Flessner; Christine Schwerdtfeger; Evangelia Kotsikorou; Gary A. Meints; Aurora Ortiz Gómez; Dolores González-Pacanowska; Amy M. Raker; Hong Wang; Ermond R. Van Beek; Socrates E. Papapoulos; Craig T. Morita; Eric Oldfield

doi:10.1021/jm040209d

Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption

John M. Sanders, Yongcheng Song, Julian M.W. Chan, Yonghui Zhang, Samuel Jennings, Thomas Kosztowski, Sarah Odeh, Ryan Flessner, Christine Schwerdtfeger, Evangelia Kotsikorou, Gary A. Meints, Aurora Ortiz Gómez, Dolores González-Pacanowska, Amy M. Raker, Hong Wang, Ermond R. Van Beek, Socrates E. Papapoulos, Craig T. Morita, Eric Oldfield

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vγ2Vδ2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in γδ T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.

Original language	English (US)
Pages (from-to)	2957-2963
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	48
Issue number	8
DOIs	https://doi.org/10.1021/jm040209d
State	Published - Apr 21 2005

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Online availability

10.1021/jm040209d

Library availability

Discover UIUC Full Text

Cite this

Sanders, J. M., Song, Y., Chan, J. M. W., Zhang, Y., Jennings, S., Kosztowski, T., Odeh, S., Flessner, R., Schwerdtfeger, C., Kotsikorou, E., Meints, G. A., Gómez, A. O., González-Pacanowska, D., Raker, A. M., Wang, H., Van Beek, E. R., Papapoulos, S. E., Morita, C. T., & Oldfield, E. (2005). Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption. Journal of Medicinal Chemistry, 48(8), 2957-2963. https://doi.org/10.1021/jm040209d

Sanders, JM, Song, Y, Chan, JMW, Zhang, Y, Jennings, S, Kosztowski, T, Odeh, S, Flessner, R, Schwerdtfeger, C, Kotsikorou, E, Meints, GA, Gómez, AO, González-Pacanowska, D, Raker, AM, Wang, H, Van Beek, ER, Papapoulos, SE, Morita, CT & Oldfield, E 2005, 'Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption', Journal of Medicinal Chemistry, vol. 48, no. 8, pp. 2957-2963. https://doi.org/10.1021/jm040209d

@article{a333370884d2405fb4b47a01c3a8c046,

title = "Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption",

abstract = "We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vγ2Vδ2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in γδ T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.",

author = "Sanders, {John M.} and Yongcheng Song and Chan, {Julian M.W.} and Yonghui Zhang and Samuel Jennings and Thomas Kosztowski and Sarah Odeh and Ryan Flessner and Christine Schwerdtfeger and Evangelia Kotsikorou and Meints, {Gary A.} and G{\'o}mez, {Aurora Ortiz} and Dolores Gonz{\'a}lez-Pacanowska and Raker, {Amy M.} and Hong Wang and {Van Beek}, {Ermond R.} and Papapoulos, {Socrates E.} and Morita, {Craig T.} and Eric Oldfield",

year = "2005",

month = apr,

day = "21",

doi = "10.1021/jm040209d",

language = "English (US)",

volume = "48",

pages = "2957--2963",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "8",

}

TY - JOUR

T1 - Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption

AU - Sanders, John M.

AU - Song, Yongcheng

AU - Chan, Julian M.W.

AU - Zhang, Yonghui

AU - Jennings, Samuel

AU - Kosztowski, Thomas

AU - Odeh, Sarah

AU - Flessner, Ryan

AU - Schwerdtfeger, Christine

AU - Kotsikorou, Evangelia

AU - Meints, Gary A.

AU - Gómez, Aurora Ortiz

AU - González-Pacanowska, Dolores

AU - Raker, Amy M.

AU - Wang, Hong

AU - Van Beek, Ermond R.

AU - Papapoulos, Socrates E.

AU - Morita, Craig T.

AU - Oldfield, Eric

PY - 2005/4/21

Y1 - 2005/4/21

N2 - We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vγ2Vδ2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in γδ T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.

AB - We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vγ2Vδ2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in γδ T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.

UR - http://www.scopus.com/inward/record.url?scp=20944447015&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20944447015&partnerID=8YFLogxK

U2 - 10.1021/jm040209d

DO - 10.1021/jm040209d

M3 - Article

C2 - 15828834

AN - SCOPUS:20944447015

SN - 0022-2623

VL - 48

SP - 2957

EP - 2963

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -

Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption

Abstract

ASJC Scopus subject areas

Online availability

Library availability

Related links

Fingerprint

Cite this