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

• Published in: Bioorganic & medicinal chemistry letters 2006-10, Vol.16 (20), p.5368-5372
• Main 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.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Amides - chemistry; Animals; Anti-tumor; Antiangiogenenic therapy; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biological Availability; Carbamates - chemistry; Carbazoles - chemical synthesis; Carbazoles - chemistry; Carbazoles - pharmacology; Enzyme Activation - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; Medical sciences; Mice; Mice, Nude; Molecular Structure; Pharmacology. Drug treatments; Rats; Receptor, TIE-2 - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship; TIE-2; Tyrosine kinases; Urea - chemistry; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGF-R2
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.07.066

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. 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.