Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors |
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Authors: | Becknell Nadine C Zulli Allison L Angeles Thelma S Yang Shi Albom Mark S Aimone Lisa D Robinson Candy Chang Hong Hudkins Robert L |
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Affiliation: | Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. nbecknell@cephalon.com |
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Abstract: | A novel series of C-3 urea, amide, and carbamate fused dihydroindazolocarbazole (DHI) analogs are reported as highly potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases with excellent cellular potency. Structure-activity relationship (SAR) studies indicate the optimal N-13 alkyl substitutions are n-propyl and i-butyl. The isopropyl carbamate 39 displayed good dual enzyme, cell potency, and rat pharmacokinetic properties for advancement to in vivo evaluation. |
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