title: A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy.
abstract: CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with a long residence time on the human CCR2, is effective in inhibiting the development of atherosclerosis in a mouse disease model. First, radioligand binding assays were performed to determine affinity and binding kinetics of 15a on murine CCR2. To assess the in vivo efficacy, western-type diet fed apoE-/-mice were treated daily with 15a or vehicle as control. Treatment with 15a reduced the amount of circulating CCR2+monocytes and the size of the atherosclerotic plaques in both the carotid artery and the aortic root. We then showed that the long pharmacokinetic half-life of 15a combined with the high drug concentrations ensured prolonged CCR2 occupancy. These data render 15a a promising compound for drug development and confirms high receptor occupancy as a key parameter when targeting chemokine receptors.
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Ilze
authors.identifier: 0000-0002-1242-1959
authors.initials: I
authors.lastname: Bot
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Ortiz Zacarías
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Wilhelmus E A
authors.initials: WE
authors.lastname: de Witte
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van Santbrink
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Daniël
authors.initials: D
authors.lastname: van der Velden
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Mara J
authors.initials: MJ
authors.lastname: Kröner
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: van der Berg
authors.affiliation: Vertex Pharmaceuticals, San Diego, CA, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Stamos
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Elizabeth C M
authors.initials: EC
authors.lastname: de Lange
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
authors.forename: Adriaan P
authors.identifier: 0000-0002-1182-2259
authors.initials: AP
authors.lastname: IJzerman
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands. l.h.heitman@lacdr.leidenuniv.nl.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016466:CHO Cells; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D003412:Cricetulus; D003517:Cyclopentanes / Q000493:pharmacokinetics / Q000494:pharmacology*; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D007546:Isoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D003517:Cyclopentanes; D007546:Isoquinolines; D054390:Receptors, CCR2