title: Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists.
abstract: Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Center for Drug Research, Leiden University , Post Office Box 9502, 2300 RA Leiden, Netherlands.
authors.forename: Maris
authors.initials: M
authors.lastname: Vilums
authors.forename: Annelien J M
authors.initials: AJ
authors.lastname: Zweemer
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Yu
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.forename: Julia M
authors.initials: JM
authors.lastname: Hillger
authors.forename: Hannah
authors.initials: H
authors.lastname: Wapenaar
authors.forename: Ilse A E
authors.initials: IA
authors.lastname: Bollen
authors.forename: Farhana
authors.initials: F
authors.lastname: Barmare
authors.forename: Raymond
authors.initials: R
authors.lastname: Gross
authors.forename: Jeremy
authors.initials: J
authors.lastname: Clemens
authors.forename: Paul
authors.initials: P
authors.lastname: Krenitsky
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Dean
authors.initials: D
authors.lastname: Stamos
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: D001667:Binding, Competitive; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D003517:Cyclopentanes; D007189:Indans; D007192:Indenes; D008024:Ligands; D054390:Receptors, CCR2; D013764:Tetrahydronaphthalenes; C016329:cyclopentylamine