Design and synthesis of dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases.
Dandu R,
Zulli AL,
Bacon ER,
Underiner T,
Robinson C,
Chang H,
Miknyoczki S,
Grobelny J,
Ruggeri BA,
Yang S,
Albom MS,
Angeles TS,
Aimone LD,
Hudkins RL.
Department of Medicinal Chemistry, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. dreddy@cephalon.com
Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure-activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity.
PMID: 18308565 [PubMed - indexed for MEDLINE]