Pyrrolidinohydroquinazolines––a novel class of CCR3 modulators

Anderskewitz, Ralf; Bauer, Rolf; Bodenbach, Gisela; Gester, Dirk; Gramlich, Bernd; Morschhäuser, Gerd; Birke, F.W.

doi:10.1016/j.bmcl.2004.11.039

Cited by 37 publications

(18 citation statements)

References 14 publications

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“…Nevertheless, a handful of agonists for chemokine receptors other than CXCR3 has already been found in recent years. [127][128][129] CXCR3 agonists were disclosed by researchers from Pharmacopeia in 2006. In an HTS screen for antagonists of a pool of more than four million compounds, they identified a few CXCR3 agonist chemotypes.…”

Section: Nonpeptidergic Cxcr3 Agonistsmentioning

confidence: 99%

Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

et al. 2008

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The CXCR3 chemokine receptor was first discovered in 1996 and has been shown to play an important role in several diseases, most of which are related to inflammation. This review describes in detail the development of small CXCR3 ligands and their therapeutic potential. Classes of CXCR3 antagonists with strikingly variable core structures have emerged. Some of these compounds have confirmed the beneficial role of CXCR3 antagonism in animal models of disease. One of the compounds, AMG487, progressed to Phase II clinical trials but has been withdrawn because of lack of efficacy. New antagonist classes are being developed to reveal the full therapeutic potential of CXCR3.

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Section: Nonpeptidergic Cxcr3 Agonistsmentioning

confidence: 99%

Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

et al. 2008

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“…It is of interest that the CCR3 binding site occupied by the antagonist UCB35625 appears to overlap that of a structurally related small molecule agonist and that a single mutation in the receptor binding site CCR3 can confer agonist activity to UCB35625 [25]. This suggests that there is a fine line between agonist and antagonist activity at CCR3; and CCR3 antagonist programs from other 344j 15 Targeting CCR3 15.5 Targeting CCR3 Function j347 groups have also reported the identification of small molecule agonists of the receptor following the optimization of the structure-activity relationships of lead compounds [73,74]. This may be a common feature of chemokine receptors as recent reports have also described small molecule agonists of CCR5, CCR8 and CXCR3 arising from other drug discovery programs [75][76][77].…”

Section: Targeting Ccr3 Functionmentioning

confidence: 99%

Targeting CCR3

Pease

2010

Methods and Principles in Medicinal Chemistry

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Allergic responses are a result of an undesirable response to an otherwise innocuous antigen or allergen and are characterized by an increase in the number of eosinophils, Th2 lymphocytes, basophils and mast cells within the inflammed tissue. The specific recruitment of these leukocytes to the site of inflammation is principally mediated by a chemokine receptor known as CCR3, which signals in response to the eotaxin family of chemokines. Since the incidence of allergic diseases such as asthma and atopic dermatitis are approaching epidemic proportions in the Western World, much effort has been focused upon the specific targeting of CCR3 as a potential therapeutic avenue. This chapter reviews our understanding of the biology underpinning this ligand-receptor axis and discusses recent developments in antagonizing the interactions of CCR3 with its ligands. CCR3 and the Eotaxin Family of ChemokinesThe discovery of CCR3 and its chemokine ligands followed intensive efforts by several groups. The principal working hypothesis was that the selective recruitment of eosinophils oberved during the late response to allergen in sensitized individuals was mediated by endogenous selective eosinophil chemoattractant(s) and complimentary cell surface receptors on the eosinophil. The first CCR3 ligand to be discovered was named eotaxin and was identified following the fractionation of bronchoalveolar lavage fluid from allergen-sensitized guinea pigs [1]. Protein sequencing suggested that it was a member of the recently discovered CC family of chemokines including RANTES/CCL5, a chemokine which had previously been shown to be chemotactic for eosinophils but was

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“…[3][4][5] Among these types of molecules, quinazolinimines have been studied due to their extensive therapeutic potential, for example as selective butyrylcholinesterase inhibitors for Alzheimer's disease and for antiproliferative activities in cancer. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] In general, some reported protocols for synthesizing heterocyclic compounds require long reaction times, 17 high temperature, 19 special setup and workup conditions, 7,8 and subsequently low yields. 7 In this context, our research group has recently reported an accessible way to obtain a set of substituted 2-(phenyl or methyl)-3-aryl-4(3H)-quinazoliniminium chlorides containing diverse substituents around the heterocycle through two alternative pathways.…”

Section: Introductionmentioning

confidence: 99%