Abstract
Novel 2,5-dioxoimidazolidine-based conformationally constrained analogues of KN62 (1) were developed as P2X7 receptor (P2X7R) antagonists using a rigidification strategy of the tyrosine backbone of 1. SAR analysis of the 2,5-dioxoimidazolidine scaffold indicated that piperidine substitution at the N3 position and no substitution at N1 position were preferable. Further optimization of the substituents at the piperidine nitrogen and the spacer around the skeleton resulted in several superior antagonists to 1, including 1-adamantanecarbonyl analogue 21i (IC50 = 23 nM in ethidium uptake assay; IC50 = 14 nM in IL-1β ELISA assay) and (3-CF3-4-Cl)benzoyl analogue (-)-21w (54 nM in ethidium uptake assay; 9 nM in IL-1β ELISA assay), which was more potent than the corresponding (+) isomer. Compound 21w displayed potent inhibitory activity in an ex vivo model of LTP-induced pain signaling in the spinal cord and significant anti-inflammatory activity in in vivo models of carrageenan-induced paw edema and type II collagen-induced joint arthritis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / chemistry
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
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Animals
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Arthritis, Experimental / chemically induced
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Arthritis, Experimental / drug therapy*
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Carrageenan / toxicity
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Cattle
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Collagen Type II / toxicity
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Drug Discovery*
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Edema / chemically induced
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Edema / drug therapy
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Enzyme-Linked Immunosorbent Assay
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HEK293 Cells
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Humans
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Hydantoins / chemistry
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Hydantoins / pharmacology*
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Immunoblotting
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Inflammation / chemically induced
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Inflammation / drug therapy*
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Interleukin-1beta / metabolism
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Long-Term Potentiation
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Macrophages / cytology
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Macrophages / drug effects
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Male
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Mice, Inbred DBA
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Molecular Structure
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Monocytes / cytology
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Monocytes / drug effects
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Neuralgia / drug therapy*
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Neuralgia / etiology
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Purinergic P2X Receptor Antagonists / chemistry
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Purinergic P2X Receptor Antagonists / pharmacokinetics
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Purinergic P2X Receptor Antagonists / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptors, Purinergic P2X7 / chemistry*
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Structure-Activity Relationship
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Sulfonic Acids / chemistry
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Sulfonic Acids / pharmacology*
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Tissue Distribution
Substances
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4-((3-(1-(4-chloro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-2,5-dioxoimidazolidin-4-yl)methyl)phenyl isoquinoline-5-sulfonate
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Collagen Type II
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Hydantoins
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Interleukin-1beta
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Purinergic P2X Receptor Antagonists
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Receptors, Purinergic P2X7
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Sulfonic Acids
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KN 62
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Carrageenan