title: 8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors.
abstract: A novel series of 8-(2-tetrahydropyranyl)-12,13-dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazoles (THP-DHI) was synthesized and evaluated as dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors. Development of the structure-activity relationships (SAR) with the support of X-ray crystallography led to identification of 7f and 7g as potent, selective dual TIE-2/VEGF-R2 inhibitors with excellent cellular potency and acceptable pharmacokinetic properties. Compounds 7f and 7g were orally active in tumor models with no observed toxicity.
authors.affiliation: Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. rhudkins@cephalon.com
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
authors.forename: Allison L
authors.initials: AL
authors.lastname: Zulli
authors.forename: Ted L
authors.initials: TL
authors.lastname: Underiner
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Sheryl L
authors.initials: SL
authors.lastname: Meyer
authors.forename: Daniel
authors.initials: D
authors.lastname: Pauletti
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Elena V
authors.initials: EV
authors.lastname: Fedorov
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Fedorov
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2