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Your search keyword '"William R. Antonios-McCrea"' showing total 4 results
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4 results on '"William R. Antonios-McCrea"'

1. Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors

Author

Molly He, Timothy D. Machajewski, Daniel Menezes, Frazier Kelly, William R. Antonios-Mccrea, Jayesh Vora, Vincent P. Le, Warne Robert L, Gena Lapointe, Cynthia M. Shafer, Jazan Elisa, Sabina Pecchi, Paul Feucht, Helen Ye, Clarke Albany Taylor, Johanna M. Jansen, Mary Ellen Wernette-Hammond, Marion Wiesmann, Alex L. Harris, Carla Heise, Christopher McBride, Paul A. Renhowe, and Kimberly Aardalen

Subjects
Models, Molecular, Magnetic Resonance Spectroscopy, Mice, SCID, Quinolones, Pharmacology, Tropomyosin receptor kinase C, Mass Spectrometry, Receptor tyrosine kinase, Mice, Structure-Activity Relationship, Growth factor receptor, Mice, Inbred NOD, Drug Discovery, Animals, Humans, Protein Kinase Inhibitors, Chromatography, High Pressure Liquid, Insulin-like growth factor 1 receptor, Dose-Response Relationship, Drug, biology, Chemistry, Receptor Protein-Tyrosine Kinases, Drug Design, ROR1, biology.protein, Molecular Medicine, Tyrosine kinase, Platelet-derived growth factor receptor, Proto-oncogene tyrosine-protein kinase Src
Abstract

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values

Published
2008

2. LHMDS mediated tandem acylation–cyclization of 2-aminobenzenecarbonitriles with 2-benzymidazol-2-yl acetates: a short and efficient route to the synthesis of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones

Author

Timothy D. Machajewski, Paul A. Renhowe, Sabina Pecchi, Clarke Taylor, Jazan Elisa, Kelly A. Frazier, Cynthia M. Shafer, Christopher McBride, and William R. Antonios-McCrea

Subjects
Acylation, Tandem, Chemistry, Organic Chemistry, Drug Discovery, Organic chemistry, Biochemistry
Abstract

We herein describe the discovery of a mild, one-pot tandem acylation–cyclization for the synthesis of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones from 2-aminobenzenecarbonitriles and ethyl 2-benzimidazol-2-yl acetates.

Published
2006

3. Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma

Author

Joelle Verhagen, Brent A. Appleton, Cynthia M. Shafer, Sharadha Subramanian, Louie Alicia, Abran Costales, William R. Antonios-Mccrea, Kimberly Aardalen, Maureen Mckenna, Darrin Stuart, Paul A. Renhowe, Leonard Sung, Barry Levine, Teresa E. Williams, Timothy D. Machajewski, Savithri Ramurthy, James Chou, Daniel Poon, Christopher McBride, and Payman Amiri

Subjects
MAPK/ERK pathway, Metastatic melanoma, business.industry, Kinase, Organic Chemistry, Bioinformatics, Biochemistry, Clinical trial, Pharmacokinetics, In vivo, Pharmacodynamics, Drug Discovery, Cancer research, Medicine, business, Tyrosine kinase
Abstract

Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.

Published
2014

4. Design, structure-activity relationship, and in vivo characterization of the development candidate NVP-HSP990

Author

Julie Lin, Daniel Menezes, Mendenhall Kris G, Paul A. Renhowe, Michael Wang, Yi Xia, Pietro Taverna, Louie Alicia, Dachuan Lei, Susan Fong, Yasheen Zhou, Christopher McBride, Daniel Poon, Barry Levine, Cynthia M. Shafer, Zhenhai Gao, William R. Antonios-Mccrea, Alice Rico, Thomas Hendrickson, Tinya Abrams, Nancy Pryer, Doughan Brandon M, Yongjin Xu, Paul A. Barsanti, Maureen Mckenna, Timothy D. Machajewski, Xiaodong Lin, Abran Costales, Cornelia Bellamacina, Brinner Kristin, and Teresa E. Williams

Subjects
Drug, Chemistry, Pyridones, media_common.quotation_subject, Antineoplastic Agents, Pharmacology, Mice, Structure-Activity Relationship, Pyrimidines, Pharmacokinetics, In vivo, Oral administration, Pharmacodynamics, Drug Discovery, Molecular Medicine, Structure–activity relationship, Animals, NVP-HSP990, HSP90 Heat-Shock Proteins, media_common
Abstract

Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from a commercial hit. The exploration of this series led to the selection of NVP-HSP990 as a development candidate.

Published
2014

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