Design of novel and potent cPLA2α inhibitors containing an α-methyl-2-ketothiazole as a metabolically stable serine trap

Design of novel and potent cPLA2α inhibitors containing an α-methyl-2-ketothiazole as a metabolically stable serine trap

We report the design of novel, potent cPLA(2)α inhibitors that possess an α-methyl-2-ketothiazole that acts as a serine-reactive moiety. We describe the optimization of the series for potency and metabolic stability towards ketone reduction. This was achieved by attenuating the reactivity of the ket...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2011-05, Vol.21 (10), p.3128-3133
Hauptverfasser: METE, Antonio, ANDREWS, Glen, ROBINSON, David H, SMITH, Gill M, WELLS, Edward, WITHNALL, W. John, BERNSTEIN, Mike, CONNOLLY, Stephen, HARTOPP, Paul, JACKSON, Clive G, LEWIS, Richard, MARTIN, Lain, MURRAY, David, RILEY, Rob
Format: Artikel
Sprache:eng
Schlagworte:
Animals
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Drug Design
Drug Stability
Enzyme Activation - drug effects
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Group IV Phospholipases A2 - antagonists & inhibitors
HL-60 Cells
Humans
Inhibitory Concentration 50
Ketones - chemical synthesis
Ketones - chemistry
Ketones - pharmacology
Magnetic Resonance Spectroscopy
Medical sciences
Molecular Structure
Oxidation-Reduction
Pharmacology. Drug treatments
Rats
Serine - chemistry
Thiazoles - chemical synthesis
Thiazoles - chemistry
Thiazoles - pharmacology
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Zusammenfassung:We report the design of novel, potent cPLA(2)α inhibitors that possess an α-methyl-2-ketothiazole that acts as a serine-reactive moiety. We describe the optimization of the series for potency and metabolic stability towards ketone reduction. This was achieved by attenuating the reactivity of the ketone using a combination of electronic and steric effects.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.03.005