A New Class of Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors:  Structure−Activity Relationships for a Series of 9-Alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones and the Identification of CEP-5214 and Its Dimethylglycine Ester Prodrug Clinical Candidate CEP-7055

Abstract

A series of potent vascular endothelial growth factor R2 (VEGF-R2) tyrosine kinase inhibitors from a new indenopyrrolocarbazole template is reported. The structure-activity relationships for a series of 9-alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones revealed an optimal R9 substitution with ethoxymethyl 19 (VEGF-R2 IC(50) = 4 nM) and isopropoxymethyl 21 (VEGF-R2 IC(50) = 8 nM) being the most potent inhibitors in the series. The VEGF-R2 activity was reduced appreciably by increasing the size of the R9 alkoxy group or by alpha-methyl branching adjacent to the ring. The combined R9 alkoxymethyl and N12 hydroxypropyl substitutions were required for potent VEGF-R2 activity, and the corresponding thioether analogues were weaker than their ether counterparts. Compound 21 (R9 isopropoxymethyl, CEP-5214) was identified as a potent, low-nanomolar pan inhibitor of human VEGF-R tyrosine kinases, displaying IC(50) values of 16, 8, and 4 nM for VEGF-R1/FLT-1, VEGF-R2/KDR, and VEGF-R3/FLT-4, respectively, with cellular activity equivalent to the isolated enzyme activity. Compound 21 exhibited good selectivity against numerous tyrosine and serine/threonine kinases including PKC, Tie2, TrkA, CDK1, p38, JNK, and IRK. To increase water solubility and oral bioavailability, the N,N-dimethylglycine ester 40 was prepared. In pharmacokinetic studies in mice and rats, increased plasma levels of 21 were observed after oral administration of 40. Compound 21 demonstrated significant in vivo antitumor activity in numerous tumor models and was advanced into phase I clinical trials as the water-soluble N,N-dimethylglycine ester prodrug 40 (CEP-7055).

Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma

“…Others have shown similar effects in other STS subtypes, including neurogenic sarcoma (28), Ewing sarcoma (29), and angiosarcoma (30). VEGF/ VEGFR2 inhibitors have been evaluated for human STS treatment.…”

Metabolism of 5-Isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737): Identification of an UnusualN-Acetylglucosamine Conjugate in the Cynomolgus Monkey

“…The efficacy of the monoclonal, anti-VEGF antibody bevacizumab (Avastin; Genentech, South San Francisco, CA) in treating metastatic renal cell and rectal carcinomas (Willett et al, 2004) provided a clinical proof-of-concept for sequestering VEGF in cancer therapy. Small-molecule VEGF receptor antagonists with varying selectivity have also shown promise in the clinic (Bold et al, 2000;Hennequin et al, 2002;Abrams et al, 2003;Beebe et al, 2003;Gingrich et al, 2003;Traxler, 2003;Wedge et al, 2005;Zakarija and Soff, 2005).…”

The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice

“…1), N,N-dimethylglycine 3-{5,6,7,13-tetrahydro-9-[(1-methylethoxy) methyl]-5-oxo-12H-indeno(2,1-a )pyrrolo(3,4-c )carbazol-12-yl}propyl ester, the ester prodrug of CEP-5214, was prepared to increase its aqueous solubility and facilitate oral delivery (Cephalon, Inc., West Chester, PA). The synthetic routes for CEP-7055 and CEP-5214 have been described (29). Details of the pharmacology and pharmacokinetics of CEP-7055 have been described previously (28).…”

“…In this report, we describe the effects of chronic administration of CEP-7055 (28,29), the prodrug of CEP-5214, a low nanomolar, orally active inhibitor of all three VEGFR kinase receptor subtypes (VEGFR1/FLT-1 IC 50 , 16 nmol/L; VEGFR2/KDR IC 50 , 8 nmol/L; and VEGFR3/FLT-4 IC 50 , 4 nmol/L) alone and in combination with standard of care chemotherapeutic agents for their effects on primary and metastatic tumor burden and survival in two highly specialized and aggressive orthotopic tumor models in mice. CEP-7055 was evaluated in combination with temozolomide in a human orthotopic glioblastoma multiforme model in nude mice and with irinotecan or oxaliplatin using the metastatic murine CT-26 colon carcinoma model in BALB/c mice.…”