title: Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase.
abstract: The nitrogen-containing bisphosphonates (N-BPs) are the main drugs currently used to treat diseases characterized by excessive bone resorption. The major molecular target of N-BPs is farnesylpyrophosphate synthase. N-BPs inhibit the enzyme by a mechanism that involves time dependent isomerization of the enzyme. We investigated features of N-BPs that confer maximal slow and tight-binding by quantifying the initial and final K(i)s and calculating the isomerization constant K(isom) for many N-BPs. Disruption of the phosphonate-carbon-phosphonate backbone resulted in loss of potency and reduced K(isom). The lack of a hydroxyl group on the geminal carbon also reduced K(isom). The position of the nitrogen in the side chain was crucial to both K(i) and K(isom). A correlation of K(isom) and also final K(i) with previously published in vivo potency reveals that the isomerization constant ( R = -0.77, p < 0.0001) and the final inhibition of FPPS by N-BPs ( R = 0.74, p < 0.0001) are closely linked to antiresorptive efficacy.
authors.affiliation: Structural Genomics Consortium, The Botnar Research Centre, University of Oxford, Oxford, United Kingdom. james.dunford@ndos.ox.ac.uk
authors.forename: James E
authors.initials: JE
authors.lastname: Dunford
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Kwaasi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rogers
authors.forename: Bobby L
authors.initials: BL
authors.lastname: Barnett
authors.forename: Frank H
authors.initials: FH
authors.lastname: Ebetino
authors.forename: R Graham G
authors.initials: RG
authors.lastname: Russell
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Kavanagh
mesh_terms: D001665:Binding Sites; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D051228:Geranyltranstransferase; D009584:Nitrogen