AZD6703
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 α and β forms of p38 and is inactive at the γ and δ forms. It is >100-fold selective for other kinases tested. 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 has been assessed in a single ascending dose study in healthy volunteers and at doses up to 64mg was well tolerated. There were no 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 preclinical 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.
Mechanism of Action
Mitogen-activated protein kinase 14 (p38 α) Inhibitor
Original Therapeutic Area
Other
CNS Penetrant
Unknown
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Brown DS., et al. (2012).
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. Jun 15;22(12):3879-83. doi: 10.1016/j.bmcl.2012.04.116.