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

Antonio Mete; Glen Andrews; Mike Bernstein; Stephen Connolly; Paul Hartopp; Clive G Jackson; Richard Lewis; Iain Martin; David Murray; Rob Riley; David H Robinson; Gill M Smith; Edward Wells; W John Withnall

doi:10.1016/j.bmcl.2011.03.005

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

Bioorg Med Chem Lett. 2011 May 15;21(10):3128-33. doi: 10.1016/j.bmcl.2011.03.005. Epub 2011 Mar 6.

Authors

Antonio Mete¹, Glen Andrews, Mike Bernstein, Stephen Connolly, Paul Hartopp, Clive G Jackson, Richard Lewis, Iain Martin, David Murray, Rob Riley, David H Robinson, Gill M Smith, Edward Wells, W John Withnall

Affiliation

¹ Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, United Kingdom. [email protected]

PMID: 21450464
DOI: 10.1016/j.bmcl.2011.03.005

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.

MeSH terms

Animals
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
Molecular Structure
Oxidation-Reduction
Rats
Serine / chemistry
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Enzyme Inhibitors
Ketones
Thiazoles
Serine
Group IV Phospholipases A2