TIE-2/VEGF-R2 SAR and in vitro activity of C3-acyl dihydroindazolo[5,4- a]pyrrolo[3,4- c]carbazole analogs

• Published in: Bioorganic & medicinal chemistry 2008-04, Vol.18 (7), p.2368-2372
• Main Authors: Underiner, Ted L., Ruggeri, Bruce, Aimone, Lisa, Albom, Mark, Angeles, Thelma, Chang, Hong, Hudkins, Robert L., Hunter, Kathryn, Josef, Kurt, Robinson, Candy, Weinberg, Linda, Yang, Shi, Zulli, Allison
• Format: Article
• Language: English
• Subjects: Acylation; Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - pharmacokinetics; Angiotensin I; Animals; Anti-angiogenic; Antineoplastic agents; Aorta - cytology; Aorta - drug effects; Aorta - metabolism; Biological and medical sciences; Biological Availability; Cells, Cultured; Chemotaxis - physiology; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; General aspects; Indazoles - chemical synthesis; Indazoles - pharmacology; Indoles - chemical synthesis; Indoles - pharmacology; Kinase inhibitor; Medical sciences; Models, Chemical; Pharmacology. Drug treatments; Rats; Receptor, TIE-2 - antagonists & inhibitors; Structure-Activity Relationship; Thiophenes - chemistry; TIE-2; Umbilical Veins - cytology; Umbilical Veins - drug effects; Umbilical Veins - metabolism; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGF-R2; VEGFR2
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.02.069

Orally bioavailable, dual inhibitors of TIE-2/VEGF-R2 were identified by elaborating the C3/N13 SAR around a fused pyrrolodihydroindazolocarbazole scaffold. Analogs bearing a C3-thiophencarbonyl group were evaluated in enzymatic and cellular biochemical assays; two orally bioavailable analogs were further profiled in functional assays and found to inhibit microvessel growth in rat aortic explant cultures and inhibit Ang-1-stimulated chemotaxis of HUVECs. Orally bioavailable, dual inhibitors of TIE-2/VEGF-R2 were identified by elaborating the C3/N13 SAR around a fused pyrrolodihydroindazolocarbazole scaffold. Analogs bearing a C3-thiophencarbonyl group were evaluated in enzymatic and cellular biochemical assays; two orally bioavailable analogs were further profiled in functional assays and found to inhibit microvessel growth in rat aortic explant cultures and inhibit Ang-1-stimulated chemotaxis of HUVECs.