title: Synthesis and structure-activity relationships of pyrazine-pyridine biheteroaryls as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors.
abstract: There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Palladium-catalyzed C-C bond, C-N bond formation reactions were used to assemble various pyrazine-pyridine biheteroaryls as potent VEGFR-2 inhibitors. Among them, 4-{5-[6-(3-chloro-phenylamino)-pyrazin-2-yl]-pyridin-3-ylamino}-butan-1-ol (39) and N-{5-[6-(3-chloro-phenylamino)-pyrazin-2-yl]-pyridin-3-yl}-N',N'-dimethyl-ethane-1,2-diamine (41) exhibited the highest kinase selectivity against fibroblast growth factor receptor kinase, platelet-derived growth factor receptor kinase, and glycogen synthase kinase-3. All of these compounds showed good cellular potency to inhibit VEGF-stimulated proliferation of human umbilical vein endothelial cells (HUVEC) but with modest effects on the unstimulated growth of HUVEC. The low inhibition of these compounds to the growth of tumor cell lines, such as HeLa, HCT-116, and A375 further confirms that these VEGFR-2 inhibitors are not cytotoxic agents. The in vivo antitumor activity of 39 and 41 were demonstrated in the A375 human melanoma xenograft nude mice model. Molecular modeling (QSAR analysis) was conducted in an attempt to rationalize the observed structure-activity relationship.
authors: Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202, P.O. Box 300, Raritan, New Jersey 08869, USA. gkuo@prdus.jnj.com
authors: Gee-Hong
authors: GH
authors: Kuo
authors: Catherine
authors: C
authors: Prouty
authors: Aihua
authors: A
authors: Wang
authors: Stuart
authors: S
authors: Emanuel
authors: Alan
authors: A
authors: Deangelis
authors: Yan
authors: Y
authors: Zhang
authors: Fengbin
authors: F
authors: Song
authors: Lawrence
authors: L
authors: Beall
authors: Peter J
authors: PJ
authors: Connolly
authors: Prahba
authors: P
authors: Karnachi
authors: Xin
authors: X
authors: Chen
authors: Robert H
authors: RH
authors: Gruninger
authors: Jan
authors: J
authors: Sechler
authors: Angel
authors: A
authors: Fuentes-Pesquera
authors: Steven A
authors: SA
authors: Middleton
authors: Linda
authors: L
authors: Jolliffe
authors: William V
authors: WV
authors: Murray
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: C502987:4-(5-(6-(3-chlorophenylamino)pyrazin-2-yl)pyridin-3-ylamino)butan-1-ol; D000631:Aminopyridines; D000970:Antineoplastic Agents; C502988:N-(5-(6-(3-chlorophenylamino)pyrazin-2-yl)pyridin-3-yl)-N',N'-dimethylethane-1,2-diamine; D011719:Pyrazines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2