4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties

Butora, Gabor; Morriello, Gregori J.; Kothandaraman, Shankaran; Guiadeen, Deodialsingh; Pasternak, Alexander; Parsons, William H.; MacCoss, Malcolm; Vicario, Pasquale P.; Cascieri, Margaret A.; Lu, Yang

doi:10.1016/j.bmcl.2006.07.011

Cited by 36 publications

(22 citation statements)

References 28 publications

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“…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. Subsequent optimization to generate a CCR2 antagonist with improved pharmacokinetic properties led first to the discovery of the dual CCR2 CCR5 antagonist compound 26 ( Figure 2 , compound 2), which had IC 50 s for CCR2 and CCR5 of 80 nM and 30 nM, respectively [90] (see later, under 'Promiscuous inhibitors') and later to a cyclopropylmethyl derivative that was selective for CCR2 and had excellent pharmacokinetic properties ( Figure 2 , compound 3) [84] .…”

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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“…These findings relate to disease severity and FEV1. Therefore targeting of CCL2 and its receptor could provide potentially potent and novel anti-inflammatory agents 142 . The study of such products in humans is in the early phase and clinical preparations are probably a long way off currently 143 .…”

Section: Ccl2 (Mcp-1) and Ccr2 Antagonistsmentioning

confidence: 99%

Inflammation in COPD and New Drug Strategies

Heaney¹,

Masih²

2012

Inflammation, Chronic Diseases and Cancer - Cell and Molecular Biology, Immunology and Clinical Bases

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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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4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties

Cited by 36 publications

References 28 publications

Chemokine receptor antagonists: Part 1

Chemokine receptor antagonists: Part 1

Inflammation in COPD and New Drug Strategies

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

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