Indazolylamino/anilinoquinazolines bearing a C-5 substitution as erbB2 kinase inhibitors: Structure activity relationships and identification of a candidate drug

A254 Aberrant function of the erbB family of receptor tyrosine kinases and their ligands has been described in many human cancers. Within this family, erbB2 plays a central role: mis-regulation of erbB2, for example by over-expression/gene amplification, has been observed to varying degrees in a range of tumours, particularly breast cancer.
 Medicinal chemistry effort at AstraZeneca has identified certain 5-substitued anilinoquinazolines as kinase inhibitors for Src, EGF and erbB2.
 We previouly described 1 1 as a potent and selective inhibitor of erbB2, showing antitumor efficacy after oral administration in mouse xenograft models. However, this compound was subsequently found to exhibit modest pharmacokinetics in other species (especially dog) and mild to severe effects in liver and lung in rat toxicological studies attributed to phospholipidosis, which precluded its progression towards clinical trials.
 SAR around generic structure A was developed by introducing a wide range of substituents at C4 and C5 positions to optimize the potency and incorporate desirable pharmaceutical properties. We will describe the lead candidate which was selected from this series, based on its potent erbB2 kinase inhibition profile, its physical and pharmacokinetic properties and its anti-tumor efficacy after oral administration in xenograft models with erbB2 overexpression.
 1 Ballard, P.; Bradbury, R.H.; Hennequin, L.F.A.; Hickinson, D.M.; Johnson, P.D.; Kettle, J.G.; Klinowska, T.; Morgentin, R.; Ogilvie, D.J.; Olivier, A. Bioorg. Med. Chem. Lett. 2005 , 15 , 4226-4229.