Abstract
The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipase A2alpha (cPLA2alpha, type IVA phospholipase) are described. Inhibitors of cPLA2alpha are predicted to be efficacious in treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. The introduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of these inhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a sub-micromolar inhibitor of cPLA2alpha in the GLU micelle and rat whole blood assays. Compound 123 displayed oral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Benzoates / chemical synthesis*
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Benzoates / pharmacokinetics
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Benzoates / pharmacology
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Carrageenan
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Cytosol / enzymology*
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Edema / chemically induced
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Edema / drug therapy
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Group IV Phospholipases A2
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Humans
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Male
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Phospholipases A / antagonists & inhibitors*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Benzoates
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Indoles
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Sulfonamides
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ecopladib
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Carrageenan
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Phospholipases A
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Group IV Phospholipases A2