Abstract
A novel series of zwitterions is reported that contains potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A high quality lead compound 2 was discovered from virtual screening based on the pharmacophore features present in a literature compound 1. Lead optimization through side chain modification and preliminary changes around the acid are disclosed. Optimization of physicochemical properties (log D, MWt, and HBA) allowed maintenance of high CRTh2 potency while achieving low rates of metabolism and minimization of other potential concerns such as hERG channel activity and permeability. A step-change increase in potency was achieved through addition of a single methyl group onto the piperazine ring, which gave high quality compounds suitable for progression into in vivo studies.
MeSH terms
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Animals
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Blood Proteins / metabolism
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CHO Cells
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Calcium / metabolism
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Cell Shape / drug effects
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Cricetinae
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Cricetulus
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Cytochrome P-450 Enzyme Inhibitors
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ERG1 Potassium Channel
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Eosinophils / cytology
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Eosinophils / drug effects
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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HEK293 Cells
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Humans
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Piperazines / chemical synthesis*
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Protein Binding
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Radioligand Assay
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Rats
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Receptors, Immunologic / agonists
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Receptors, Immunologic / antagonists & inhibitors*
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Receptors, Immunologic / chemistry
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Receptors, Prostaglandin / agonists
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Receptors, Prostaglandin / antagonists & inhibitors*
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Receptors, Prostaglandin / chemistry
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Blood Proteins
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Cytochrome P-450 Enzyme Inhibitors
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Piperazines
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Receptors, Immunologic
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Receptors, Prostaglandin
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Calcium
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prostaglandin D2 receptor