title: Evaluation of (4-Arylpiperidin-1-yl)cyclopentanecarboxamides As High-Affinity and Long-Residence-Time Antagonists for the CCR2 Receptor.
abstract: Animal models suggest that the chemokine ligand 2/CC-chemokine receptor 2 (CCL2/CCR2) axis plays an important role in the development of inflammatory diseases. However, CCR2 antagonists have failed in clinical trials because of a lack of efficacy. We previously described a new approach for the design of CCR2 antagonists by the use of structure-kinetics relationships (SKRs). Herein we report new findings on the structure-affinity relationships (SARs) and SKRs of the reference compound MK-0483, its diastereomers, and its structural analogues as CCR2 antagonists. The SARs of the 4-arylpiperidine group suggest that lipophilic hydrogen-bond-accepting substituents at the 3-position are favorable. However, the SKRs suggest that a lipophilic group with a certain size is desired [e.g., 3-Br: Ki =2.8 nM, residence time (t(res))=243 min; 3-iPr: Ki =3.6 nM, t(res) =266 min]. Alternatively, additional substituents and further optimization of the molecule, while keeping a carboxylic acid at the 3-position, can also prolong t(res); this was most prominently observed in MK-0483 (Ki =1.2 nM, t(res) =724 min) and a close analogue (Ki =7.8 nM) with a short residence time.
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands).
authors.forename: Maris
authors.initials: M
authors.lastname: Vilums
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands).
authors.forename: Annelien J M
authors.initials: AJ
authors.lastname: Zweemer
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands).
authors.forename: Arian
authors.initials: A
authors.lastname: Dilanchian
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands).
authors.forename: Jacobus P D
authors.initials: JP
authors.lastname: van Veldhoven
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands).
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands).
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.affiliation: Vertex Pharmaceuticals Inc. 11010 Torreyana Road, San Diego, CA 92121 (USA).
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.affiliation: Vertex Pharmaceuticals Inc. 11010 Torreyana Road, San Diego, CA 92121 (USA).
authors.forename: Dean
authors.initials: D
authors.lastname: Stamos
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands).
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands). ijzerman@lacdr.leidenuniv.nl.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000818:Animals; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D003517:Cyclopentanes; D010880:Piperidines; D054390:Receptors, CCR2
keywords: antagonists; cytokines; kinetics; structure-affinity relationships; structure-kinetics relationships