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

doi:10.1016/j.bmcl.2012.04.116

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

Bioorg Med Chem Lett. 2012 Jun 15;22(12):3879-83. doi: 10.1016/j.bmcl.2012.04.116. Epub 2012 May 2.

Authors

Dearg S Brown¹, 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

Affiliation

¹ AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.

PMID: 22608965
DOI: 10.1016/j.bmcl.2012.04.116

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.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Blood Proteins / chemistry
Crystallography, X-Ray
Dogs
Drug Discovery
Humans
Inflammation / drug therapy
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 14 / metabolism
Models, Molecular
Molecular Weight
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / pharmacology
Protein Binding
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Rats
Solubility
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Blood Proteins
N-(3,4-dichlorophenyl)-4-((2R)-4-isopropylpiperazine-2-carbonyl)piperazine-1-carboxamide
Piperazines
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase 14