Philip R Olivieri

Publications (7)32.81 Total impact

• Article: Synthesis of 4-substituted chlorophthalazines, dihydrobenzoazepinediones, 2-pyrazolylbenzoic acid, and 2-pyrazolylbenzohydrazide via 3-substituted 3-hydroxyisoindolin-1-ones.

  Hanh Nho Nguyen, Victor J Cee, Holly L Deak, Bingfan Du, Kathleen Panter Faber, Hakan Gunaydin, Brian L Hodous, Steven L Hollis, Paul H Krolikowski, Philip R Olivieri, Vinod F Patel, Karina Romero, Laurie B Schenkel, Stephanie D Geuns-Meyer
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  ABSTRACT: Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, N,N-dimethylaminophthalimide (8a) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones 9b, 9i-9am. Many of these hydroxyisoindolinones are converted to chlorophthalazines 1b-1v via reaction with hydrazine, followed by chlorination with POCl(3). We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to N,N-dimethylaminophthalimide (8a) provided dihydrobenzoazepinediones 15a-15c via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids 16a-16d and 2-pyrazolyl benzohydrazides 17a-17g rather than the expected alkynyl phthalazinones.
  The Journal of Organic Chemistry 04/2012; 77(8):3887-906. · 4.45 Impact Factor
• Article: Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines.

  Marc Payton, Tammy L Bush, Grace Chung, Beth Ziegler, Patrick Eden, Patricia McElroy, Sandra Ross, Victor J Cee, Holly L Deak, Brian L Hodous, [......], Philip R Olivieri, Karina Romero, Laurie B Schenkel, Annette Bak, Mary Stanton, Isabelle Dussault, Vinod F Patel, Stephanie Geuns-Meyer, Robert Radinsky, Richard L Kendall
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  ABSTRACT: In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.
  Cancer Research 10/2010; 70(23):9846-54. · 7.86 Impact Factor
• Article: Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.

  Victor J Cee, Laurie B Schenkel, Brian L Hodous, Holly L Deak, Hanh N Nguyen, Philip R Olivieri, Karina Romero, Annette Bak, Xuhai Be, Steve Bellon, [......], Michael J Morrison, Vinod F Patel, Robert Radinsky, Paul E Rose, Sandra Ross, Ji-Rong Sun, Jin Tang, Huilin Zhao, Marc Payton, Stephanie D Geuns-Meyer
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  ABSTRACT: The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.
  Journal of Medicinal Chemistry 09/2010; 53(17):6368-77. · 4.80 Impact Factor
• Article: Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase.

  Victor J Cee, Alan C Cheng, Karina Romero, Steve Bellon, Christopher Mohr, Douglas A Whittington, Annette Bak, James Bready, Sean Caenepeel, Angela Coxon, [......], Joseph L Kim, Jasmine Lin, Alexander M Long, Hanh Nguyen, Philip R Olivieri, Vinod F Patel, Ling Wang, Yihong Zhou, Paul Hughes, Stephanie Geuns-Meyer
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  ABSTRACT: Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase.
  Bioorganic & medicinal chemistry letters 12/2008; 19(2):424-7. · 2.65 Impact Factor
• Article: Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors.

  Brian L Hodous, Stephanie D Geuns-Meyer, Paul E Hughes, Brian K Albrecht, Steve Bellon, Sean Caenepeel, Victor J Cee, Stuart C Chaffee, Maurice Emery, Jenne Fretland, [......], Rebecca E Johnson, Joseph L Kim, Alexander M Long, Michael Morrison, Philip R Olivieri, Vinod F Patel, Anthony Polverino, Paul Rose, Ling Wang, Huilin Zhao
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  ABSTRACT: A novel class of selective Tie-2 inhibitors was derived from a multi-kinase inhibitor 1. By reversing the amide connectivity and incorporating aminotriazine or aminopyridine hinge-binding moieties, excellent Tie-2 potency and KDR selectivity could be achieved with 3-substituted terminal aryl rings. X-ray co-crystal structure analysis aided inhibitor design. This series was evaluated on the basis of potency, selectivity, and rat pharmacokinetic parameters.
  Bioorganic & Medicinal Chemistry Letters 06/2007; 17(10):2886-9. · 2.55 Impact Factor
• Article: Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.

  Brian L Hodous, Stephanie D Geuns-Meyer, Paul E Hughes, Brian K Albrecht, Steve Bellon, James Bready, Sean Caenepeel, Victor J Cee, Stuart C Chaffee, Angela Coxon, [......], Alexander M Long, Michael Morrison, Philip R Olivieri, Vinod F Patel, Anthony Polverino, Paul Rose, Paul Tempest, Ling Wang, Douglas A Whittington, Huilin Zhao
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  ABSTRACT: Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.
  Journal of Medicinal Chemistry 03/2007; 50(4):611-26. · 5.25 Impact Factor
• Article: Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase.

  Victor J Cee, Brian K Albrecht, Stephanie Geuns-Meyer, Paul Hughes, Steve Bellon, James Bready, Sean Caenepeel, Stuart C Chaffee, Angela Coxon, Maurice Emery, [......], Alexander M Long, David McGowan, Michael Morrison, Philip R Olivieri, Vinod F Patel, Anthony Polverino, David Powers, Paul Rose, Ling Wang, Huilin Zhao
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  ABSTRACT: The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.
  Journal of Medicinal Chemistry 03/2007; 50(4):627-40. · 5.25 Impact Factor