title: When structure-affinity relationships meet structure-kinetics relationships: 3-((Inden-1-yl)amino)-1-isopropyl-cyclopentane-1-carboxamides as CCR2 antagonists.
abstract: Chemokine ligand 2 (CCL2) mediates chemotaxis of monocytes to inflammatory sites via interaction with its G protein-coupled receptor CCR2. Preclinical animal models suggest that the CCL2-CCR2 axis has a critical role in the development and maintenance of inflammatory disease states (e.g., multiple sclerosis, atherosclerosis, insulin resistance, restenosis, and neuropathic pain), which can be treated through inhibition of the CCR2 receptor. However, in clinical trials high-affinity inhibitors of CCR2 have often demonstrated a lack of efficacy. We have previously described a new approach for the design of high-affinity CCR2 antagonists, by taking their residence time (RT) on the receptor into account. Here, we report our findings on both structure-affinity relationship (SAR) and structure-kinetic relationship (SKR) studies for a series of 3-((inden-1-yl)amino)-1-isopropyl-cyclopentane-1-carboxamides as CCR2 antagonists. SAR studies showed that this class of compounds tolerates a vast diversity of substituents on the indenyl ring with only small changes in affinity. However, the SKR is affected greatly by minor modifications of the structure. The combination of SAR and SKR in the hit-to-lead process resulted in the discovery of a new high-affinity and long-residence-time CCR2 antagonist (compound 15a, Ki = 2.4 nM; RT = 714 min).
authors: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors: Maris
authors: M
authors: Vilums
authors: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors: Annelien J M
authors: AJ
authors: Zweemer
authors: Vertex Pharmaceuticals Incorporated, 11010 Torreyana Rd., San Diego, CA 92121, USA.
authors: Farhana
authors: F
authors: Barmare
authors: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors: Anouk M F
authors: AM
authors: van der Gracht
authors: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors: Dave C T
authors: DC
authors: Bleeker
authors: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors: Zhiyi
authors: Z
authors: Yu
authors: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors: Henk
authors: H
authors: de Vries
authors: Vertex Pharmaceuticals Incorporated, 11010 Torreyana Rd., San Diego, CA 92121, USA.
authors: Raymond
authors: R
authors: Gross
authors: Vertex Pharmaceuticals Incorporated, 11010 Torreyana Rd., San Diego, CA 92121, USA.
authors: Jeremy
authors: J
authors: Clemens
authors: Vertex Pharmaceuticals Incorporated, 11010 Torreyana Rd., San Diego, CA 92121, USA.
authors: Paul
authors: P
authors: Krenitsky
authors: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors: Johannes
authors: J
authors: Brussee
authors: Vertex Pharmaceuticals Incorporated, 11010 Torreyana Rd., San Diego, CA 92121, USA.
authors: Dean
authors: D
authors: Stamos
authors: Vertex Pharmaceuticals Incorporated, 11010 Torreyana Rd., San Diego, CA 92121, USA.
authors: John
authors: J
authors: Saunders
authors: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors: Laura H
authors: LH
authors: Heitman
authors: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. Electronic address: ijzerman@lacdr.leidenuniv.nl.
authors: Adriaan P
authors: AP
authors: IJzerman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014162:Transfection
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D003517:Cyclopentanes
keywords: CC chemokine receptor 2; CC chemokine receptor antagonists; Long residence time; Structure–kinetics relationships