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Erik L Meredith,
Kimberly Beattie,
Robin Burgis,
Michael Capparelli,
Joseph Chapo, Lucian Dipietro,
Gabriel Gamber,
Istvan Enyedy,
David B Hood,
Vinayak Hosagrahara, [......],
Craig Plato,
Chang Rao,
Olga Rozhitskaya,
Nicolas Soldermann,
Clayton Springer,
Maurice van Eis,
Richard B Vega,
Wanlin Yan,
Qingming Zhu,
Lauren G Monovich
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ABSTRACT: The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.
Journal of Medicinal Chemistry 08/2010; 53(15):5422-38. · 4.80 Impact Factor
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Jean-Christophe Harmange,
Matthew M Weiss,
Julie Germain,
Anthony J Polverino,
George Borg,
James Bready,
Danlin Chen,
Deborah Choquette,
Angela Coxon,
Tom DeMelfi, [......],
Kelly Regal,
Phillip M Roveto,
Michael L Schrag,
Charlie Starnes,
Andrew Tasker,
Yohannes Teffera,
Ling Wang,
Ryan D White,
Douglas A Whittington,
Roger Zanon
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ABSTRACT: A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.
Journal of Medicinal Chemistry 04/2008; 51(6):1649-67. · 5.25 Impact Factor
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Michele H. Potashman,
James Bready,
Angela Coxon,
Thomas M. DeMelfi, Lucian DiPietro,
Nicholas Doerr,
Daniel Elbaum,
Juan Estrada,
Paul Gallant,
Julie Germain, [......],
Gondi N. Kumar,
Alexander M. Long,
Seshadri Neervannan,
Vinod F. Patel,
Anthony Polverino,
Paul Rose,
Simon van der Plas,
Douglas Whittington,
Roger Zanon,
Huilin Zhao
01/2008;
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Michele H Potashman,
James Bready,
Angela Coxon,
Thomas M DeMelfi, Lucian DiPietro,
Nicholas Doerr,
Daniel Elbaum,
Juan Estrada,
Paul Gallant,
Julie Germain, [......],
Gondi N Kumar,
Alexander M Long,
Seshadri Neervannan,
Vinod F Patel,
Anthony Polverino,
Paul Rose,
Simon van der Plas,
Douglas Whittington,
Roger Zanon,
Huilin Zhao
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ABSTRACT: Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).
Journal of Medicinal Chemistry 10/2007; 50(18):4351-73. · 5.25 Impact Factor
