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Your search keyword '"Bruce Ruggeri"' showing total 2 results
Start Over Author "Bruce Ruggeri" Publisher american chemical society (acs)
2 results on '"Bruce Ruggeri"'

1. 2,7-Disubstituted-pyrrolo[2,1-f][1,2,4]triazines: New Variant of an Old Template and Application to the Discovery of Anaplastic Lymphoma Kinase (ALK) Inhibitors with in Vivo Antitumor Activity

Author

Mark S. Albom, Bruce D. Dorsey, Joseph G. Lisko, Mangeng Cheng, Bruce Ruggeri, Arup K. Ghose, Eugen F. Mesaros, Weihua Wan, Mark A. Ator, Matthew R. Quail, Zeqi Huang, Diane E. Gingrich, Tho V. Thieu, Gregory J. Wells, Thelma S. Angeles, Gregory R. Ott, Lisa D. Aimone, and Lihui Lu

Subjects
Models, Molecular, Cell Membrane Permeability, Transplantation, Heterologous, Antineoplastic Agents, Mice, SCID, In Vitro Techniques, Rats, Sprague-Dawley, Mice, Structure-Activity Relationship, chemistry.chemical_compound, In vivo, Cell Line, Tumor, hemic and lymphatic diseases, Drug Discovery, medicine, Animals, Humans, Anaplastic lymphoma kinase, Structure–activity relationship, Anaplastic Lymphoma Kinase, Pyrroles, Anaplastic large-cell lymphoma, Triazine, Sulfonamides, Triazines, Chemistry, Kinase, Receptor Protein-Tyrosine Kinases, Bridged Bicyclo Compounds, Heterocyclic, medicine.disease, Rats, Transplantation, Diaminopyrimidine, Biochemistry, Microsomes, Liver, Lymphoma, Large-Cell, Anaplastic, Molecular Medicine, Drug Screening Assays, Antitumor, Neoplasm Transplantation
Abstract

A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.

Published
2011
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2. 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

Author

Candy Robinson, Lisa D. Aimone, John P. Mallamo, Shi Yang, Jeffry L. Vaught, Craig A. Dionne, Jasbir Singh, Mark A. Ator, Thelma S. Angeles, Bruce Ruggeri, Sheryl L. Meyer, Robert L. Hudkins, Diane E. Gingrich, Mark S. Albom, Mohamed Iqbal, and Reddy Dandu R

Subjects
Male, Models, Molecular, Stereochemistry, Hemangiosarcoma, Carbazoles, Mice, Nude, Angiogenesis Inhibitors, Enzyme-Linked Immunosorbent Assay, In Vitro Techniques, Rats, Sprague-Dawley, Mice, Structure-Activity Relationship, Drug Discovery, Animals, Humans, Structure–activity relationship, Prodrugs, Pyrroles, Phosphorylation, Threonine, Tyrosine, Cells, Cultured, Protein kinase C, biology, Chemistry, Sarcosine, Prodrug, Vascular Endothelial Growth Factor Receptor-2, Rats, Indenes, Liver, Solubility, Biochemistry, Enzyme inhibitor, biology.protein, Molecular Medicine, Female, Endothelium, Vascular, Drug Screening Assays, Antitumor, Tyrosine kinase
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).

Published
2003
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