title: 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).
authors.affiliation: Departments of Medicinal Chemistry, Cephalon, Inc, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Gingrich
authors.forename: Dandu R
authors.initials: DR
authors.lastname: Reddy
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Iqbal
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Mark
authors.initials: M
authors.lastname: Albom
authors.forename: Shi
authors.initials: S
authors.lastname: Yang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Sheryl L
authors.initials: SL
authors.lastname: Meyer
authors.forename: Candy
authors.initials: C
authors.lastname: Robinson
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: Craig A
authors.initials: CA
authors.lastname: Dionne
authors.forename: Jeffry L
authors.initials: JL
authors.lastname: Vaught
authors.forename: John P
authors.initials: JP
authors.lastname: Mallamo
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006394:Hemangiosarcoma / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010766:Phosphorylation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: C479233:3-(5,6,7,13-tetrahydro-9-((1-methylethoxy)methyl)-5-oxo-12H-indeno(2,1-a)pyrrolo(3,4-c)carbazol-12-yl)propanol; D020533:Angiogenesis Inhibitors; D002227:Carbazoles; D007192:Indenes; C479232: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; D011355:Prodrugs; D011758:Pyrroles; C025138:dimethylglycine; D040301:Vascular Endothelial Growth Factor Receptor-2; D012521:Sarcosine