title: Pharmacology of AMD3465: a small molecule antagonist of the chemokine receptor CXCR4.
abstract: CXCR4 is widely expressed in multiple cell types, and is involved in neonatal development, hematopoiesis, and lymphocyte trafficking and homing. Disruption of the CXCL12/CXCR4 interaction has been implicated in stem cell mobilization. Additionally CXCR4 is a co-receptor for HIV. Selective small molecule antagonists of CXCR4 therefore have therapeutic potential. AMD3465 is an N-pyridinylmethylene monocyclam CXCR4 antagonist which can block infection of T-tropic, CXCR4-using HIV. Using the CCRF-CEM T-cell line which expresses CXCR4 we have demonstrated that AMD3465 is an antagonist of SDF-1 ligand binding (K(i) of 41.7+/-1.2nM), and inhibits SDF-1 mediated signaling as shown by inhibition of GTP binding, calcium flux, and inhibition of chemotaxis. AMD3465 is selective for CXCR4 and does not inhibit chemokine-stimulated calcium flux in cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7, nor does it inhibit binding of LTB(4) to its receptor, BLT1. The pharmacokinetics of AMD3465 was investigated in mice and dogs. Absorption was rapid following subcutaneous administration. AMD3465 was cleared from dog plasma in a biphasic manner with a terminal half-life of 1.56-4.63h. Comparison of exposure to the intravenous and subcutaneous doses indicated 100% bioavailability following subcutaneous administration. AMD3465 caused leukocytosis when administered subcutaneously in mice and dogs, with peak mobilization occurring between 0.5 and 1.5h following subcutaneous dosing in mice and with maximum peak plasma concentration of compound preceding peak mobilization in dogs, indicating that AMD3465 has the potential to mobilize hematopoietic stem cells. These data demonstrate the therapeutic potential for the CXCR4 antagonist AMD3465.
authors.affiliation: AnorMED Inc., Langley, BC, Canada.
authors.forename: Veronique
authors.initials: V
authors.lastname: Bodart
authors.forename: Virginia
authors.initials: V
authors.lastname: Anastassov
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Darkes
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Idzan
authors.forename: Jean
authors.initials: J
authors.lastname: Labrecque
authors.forename: Gloria
authors.initials: G
authors.lastname: Lau
authors.forename: Renee M
authors.initials: RM
authors.lastname: Mosi
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Neff
authors.forename: Kim L
authors.initials: KL
authors.lastname: Nelson
authors.forename: Melanie C
authors.initials: MC
authors.lastname: Ruzek
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.forename: Zefferino
authors.initials: Z
authors.lastname: Santucci
authors.forename: Robert
authors.initials: R
authors.lastname: Scarborough
authors.forename: Rebecca S Y
authors.initials: RS
authors.lastname: Wong
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bridger
authors.forename: Ron T
authors.initials: RT
authors.lastname: Macfarland
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fricker
mesh_terms: D000042:Absorption; D000818:Animals; D019540:Area Under Curve; D016466:CHO Cells; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors; D002633:Chemotaxis / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006207:Half-Life; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D007964:Leukocytosis / Q000209:etiology; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D011485:Protein Binding; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D014162:Transfection
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006571:Heterocyclic Compounds; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D019718:Receptors, CXCR4; C085925:calcein AM; D002118:Calcium