Bioorganic & Medicinal Chemistry Letters 2012-06-15

The discovery of N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases

Dearg S. Brown, John G. Cumming, Paul Bethel, Jonathan Finlayson, Stefan Gerhardt, Ian Nash, Richard A. Pauptit, Kurt G. Pike, Alan Reid, Wendy Snelson, Steve Swallow, Caroline Thompson

Index: Bioorg. Med. Chem. Lett. 22(12) , 3879-83, (2012)

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Abstract

A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties.Copyright © 2012 Elsevier Ltd. All rights reserved.