Potent antagonists of the CCR2b receptor. Part 3: SAR of the (R)-3-aminopyrrolidine series

Elucidation of Binding Sites of Dual Antagonists in the Human Chemokine Receptors CCR2 and CCR5

“…1 was synthesized as described previously (Moree et al, 2008 Molecular Modeling Using the MembStruk4.0. The MembStruk4.0 procedure used in this work has been described in detail previously (Hall, 2005;Heo et al, 2007).…”

“…For this reason, we have modeled an ensemble of low-energy, three-dimensional receptor conformations of human CCR2 and CCR5 receptors using the MembStruk4.0 computational method (Hall, 2005;Heo et al, 2007) and predicted the binding sites of a CCR2/ CCR5 dual antagonist, TAK-779 (Baba et al, 1999), and a CCR2-specific compound N-(carbamoylmethyl)-3-trifluoromethyl benzamido-parachlorobenzyl 3-aminopyrrolidine from Teijin (described as Teijin compound 1) (Moree et al, 2008). The residues in the predicted antagonist binding sites of each receptor were subsequently validated using site-directed mutagenesis and after transient expression, chemotaxis measurements, and radiolabeled chemokine competitive binding experiments were carried out.…”

Investigation of the Binding Site of CCR2 using 4-Azetidinyl-1-aryl-cyclohexane Derivatives: A Membrane Modeling and Molecular Dynamics Study

“…25,[58][59][60][61] In particular, we have developed 3D-QSAR models for CCR2 using ligand based and receptor guided methodologies. 25 In this study, we used Teijin derivatives 23 to derive CoMFA and CoMSIA models, and we found that Ala102 and Asn207 are probably crucial for activity. Recently, we compared the binding sites of CCR2 and CCR5 to facilitate the development of dual antagonists targeting both CCR2 and CCR5.…”

“…It also functions in other cell types and is relevant during the pathogeneses of various diseases such as arthritis, multiple sclerosis, and type-2-diabetes, 52 and thus CCR2 is considered an important receptor. Several research groups have studies the SAR's of CCR2 antagonists experimentally 23,24,37 or computationally. 19,20,25,53 However, no previous study was conducted on the time dependent interactions between CCR2 and antagonists using MDS.…”

“…Initially, the pharmacophoric features of highly active compound 71 (IC 50 = 3.2 nM, pIC 50 = 8.4) of the Teijin lead 23 was compared with the binding site. The basic nitrogen in the pyrrolidine ring is probably forming an electrostatic interaction with Glu291.…”