title: Design of novel and potent cPLA2α inhibitors containing an α-methyl-2-ketothiazole as a metabolically stable serine trap.
abstract: 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.
authors: Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, United Kingdom. Antonio.Mete@Astrazeneca.com
authors: Antonio
authors: A
authors: Mete
authors: Glen
authors: G
authors: Andrews
authors: Mike
authors: M
authors: Bernstein
authors: Stephen
authors: S
authors: Connolly
authors: Paul
authors: P
authors: Hartopp
authors: Clive G
authors: CG
authors: Jackson
authors: Richard
authors: R
authors: Lewis
authors: Iain
authors: I
authors: Martin
authors: David
authors: D
authors: Murray
authors: Rob
authors: R
authors: Riley
authors: David H
authors: DH
authors: Robinson
authors: Gill M
authors: GM
authors: Smith
authors: Edward
authors: E
authors: Wells
authors: W John
authors: WJ
authors: Withnall
mesh_terms: D000818:Animals; D015195:Drug Design; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D051381:Rats; D012694:Serine / Q000737:chemistry; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007659:Ketones; D013844:Thiazoles; D012694:Serine; D054513:Group IV Phospholipases A2