MEDI 369 |
| The receptor tyrosine kinase Tie-2 is involved in the maturation and maintenance of blood vessels and acts in a complementary and coordinated fashion with VEGF receptor signalling. Inhibition of Tie-2 signalling is expected to prevent vessel differentiation, maturation and persistence and impair the capability for further tumour growth. Screening of the AstraZeneca compound collection identified a novel diaminopyrimidine alkynyl phenyl urea that inhibited the phosphorylation of Tie-2 in cells and was a suitable start point for further elaboration. Initial efforts focussed on the optimisation of the potency and pharmacokinetic (PK) parameters of the series. Issues encountered with a lack of photostability and poor oral bioavailability led to the development of a 2-aminopyrimidine alkyne phenyl urea series with much improved properties. The synthesis and structure-activity relationships (SAR) of both of these classes of kinase inhibitors will be described. |
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Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |