Mechanism of action: P38 alpha inhibitor

Preclinical pharmacology and pharmacokinetics

AZD6703 inhibits human MAPK14 with an IC50 of 17nM and prevents TNFα release from human isolated synovial cells with an IC50 of approximately 110nM.  AZD6703 is active at both the alpha and beta forms of p38 and is inactive at the gamma and delta forms.  It is >100-fold selective for other kinases.  AZD6703 is active in rodent models of RA.

AZD6703 is rapidly absorbed with a tmax of 0.5 -2.0 hrs in the rat, with high clearance rates and elimination via urine and faeces.

Safety and tolerability

AZD6703 had been assessed in a single ascending dose study in healthy volunteers and at doses up to 64mg was well tolerated.  There were no obvious clinically significant changes in laboratory measurements, vital signs, ECG or physical examination findings.  At 125mg dose a limited number of individuals reported dizziness or light-headedness, with some minor reports at the 64mg dose; it was therefore concluded to be dose-dependent.

Extensive Pre-Clinical studies have been performed.

Suitable for and exclusions

Due to the side effects seen with p38 inhibitors we are only considering applications for acute indications or short-term dosing strategies.

Additional Information

Publications for this compound

Find out more about this compound by reading related Publications:

Bioorganic & Medicinal Chemistry Letters

Brown, D.S et al. 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.  Volume 22, Issue 12, 15 June 2012, Pages 3879-3883”