Discovery of 3,5-bis(trifluoromethyl)benzyl l-arylglycinamide based potent CCR2 antagonists

Lu, Yang; Zhou, Changyou; Guo, Liangqin; Morriello, Gregori J.; Butora, Gabor; Pasternak, Alexander; Parsons, William H.; Mills, Sander G.; MacCoss, Malcolm; Vicario, Pasquale P.; Zweerink, Hans J.; Ayala, Julia M.; Goyal, Shefali; Hanlon, William A.; Cascieri, Margaret A.; Springer, Marty S.

doi:10.1016/j.bmcl.2006.04.045

Cited by 28 publications

(21 citation statements)

References 29 publications

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“…An extensive Structure Activity Relationship (SAR) approach around a screening hit from the Merck sample collection yielded compound 55, a benzyl piperidine derivative, ( Figure 2 , compound 1) which displays a good binding affinity (IC 50 = 39 nM) in cells expressing recombinant human CCR2 and inhibited CCL2-induced chemotaxis (IC 50 = 9.6 nM) [86] . The compound is selective against other chemokine receptors tested; however, its oral bioavailability is low (F = 4.5%) as a result of first-pass metabolism.…”

Section: Ccr2 Antagonistsmentioning

confidence: 99%

“…A number of companies have disclosed CCR2 antagonists, including Merck which has been very active in the field reporting CCR2 antagonists in both the peer reviewed [83][84][85][86][87][88][89][90] and the patent literature [91][92][93][94][95][96][97][98] . An extensive Structure Activity Relationship (SAR) approach around a screening hit from the Merck sample collection yielded compound 55, a benzyl piperidine derivative, ( Figure 2 , compound 1) which displays a good binding affinity (IC 50 = 39 nM) in cells expressing recombinant human CCR2 and inhibited CCL2-induced chemotaxis (IC 50 = 9.6 nM) [86] .…”

Section: Ccr2 Antagonistsmentioning

confidence: 99%

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Chemokine receptor antagonists: Part 1

Pease

Horuk

2009

Expert Opinion on Therapeutic Patents

103

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Section: Ccr2 Antagonistsmentioning

confidence: 99%

Section: Ccr2 Antagonistsmentioning

confidence: 99%

Chemokine receptor antagonists: Part 1

Pease

Horuk

2009

Expert Opinion on Therapeutic Patents

103

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“…Chemokines selectively recruit monocytes, neutrophils, and lymphocytes to sites of vascular injury and inflammation, [3][4][5] and different chemokines produce different leukocyte responses depending on the complementary natures of their chemokine receptors. 6,7 The basic feature of inflammation is the recruitment of leukocytes by tissue, and this process is mediated mainly by chemokines (chemotactic cytokines) via their receptors.…”

Section: Introductionmentioning

confidence: 99%

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

Kothandan¹,

Gadhe²,

Cho³

2013

Bulletin of the Korean Chemical Society

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Chemokine receptor (CCR2) is a G protein-coupled receptor that contains seven transmembrane helices. Recent pharmaceutical research has focused on the antagonism of CCR2 and candidate drugs are currently undergoing clinical studies for the treatment of diseases like arthritis, multiple sclerosis, and type 2 diabetes. In this study, we analyzed the time dependent behavior of CCR2 docked with a potent 4-azetidinyl-1-arylcyclohexane (4AAC) derivative using molecular dynamics simulations (MDS) for 20 nanoseconds (ns). Homology modeling of CCR2 was performed and the 4AAC derivative was docked into this binding site. The docked model of selected conformations was then utilized to study the dynamic behavior of the 4AAC enzyme complexes inside lipid membrane. MDS of CCR2-16b of 4AAC complexes allowed us to refine the system since binding of an inhibitor to a receptor is a dynamic process and identify stable structures and better binding modes. Structure activity relationships (SAR) for 4AAC derivatives were investigated and reasons for the activities were determined. Probable binding pose for some CCR2 antagonists were determined from the perspectives of binding site. Initial modeling showed that Tyr49, Trp98, Ser101, Glu291, and additional residues are crucial for 4AAC binding, but MDS analysis showed that Ser101 may not be vital. 4AAC moved away from Ser101 and the hydrogen bonding between 4AAC and Ser101 vanished. The results of this study provide useful information regarding the structure-based drug design of CCR2 antagonists and additionally suggest key residues for further study by mutagenesis.

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“…28 The two diastereoisomers were readily separated by flash column chromatography (silica gel, ethyl acetate-hexanes/3:7). Unfortunately, an attempt at hydrolytical cleavage of the oxazolidone failed to produce the acid 22, as it readily underwent a c-lactonization during the workup (23,24). To remedy this problem, the amine was introduced before the removal of the auxiliary, Scheme 2.…”

mentioning

confidence: 99%

“…Its optimization led to the discovery of the piperidine analog 8 with threefold improved potency. 23 Subsequently it was established that the basic nitrogen present in the backbone of the molecule can be omitted without significant loss of activity. 24 Intensive synthetic effort focusing on the amine portion of the lead structure produced further refinement of the piperidine ring.…”

mentioning

confidence: 99%