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Your search keyword '"Walter R. Bishop"' showing total 2 results
Start Over Author "Walter R. Bishop" Journal journal of medicinal chemistry
2 results on '"Walter R. Bishop"'

1. Potent, Selective, and Orally Bioavailable Tricyclic Pyridyl Acetamide N-Oxide Inhibitors of Farnesyl Protein Transferase with Enhanced in Vivo Antitumor Activity

Author

Chin-Chung Lin, Amin A. Nomeir, Ashit K. Ganguly, Patrick Pinto, Matthew Bryant, Ming Liu, F. G. Njoroge, Bancha Vibulbhan, Walter R. Bishop, Doll Ronald J, and V. Girijavallabhan

Subjects
Farnesyl Protein Transferase, Pyridines, Stereochemistry, medicine.drug_class, Administration, Oral, Biological Availability, Mice, Nude, Antineoplastic Agents, Carboxamide, Oncogene Protein p21(ras), Cyclic N-Oxides, Mice, chemistry.chemical_compound, In vivo, Drug Discovery, Tumor Cells, Cultured, medicine, Animals, Humans, Enzyme Inhibitors, Farnesyl-diphosphate farnesyltransferase, Alkyl and Aryl Transferases, biology, Biological activity, chemistry, Enzyme inhibitor, biology.protein, Molecular Medicine, Female, Piperidine, Drug Screening Assays, Antitumor, Neoplasm Transplantation, Acetamide
Abstract

We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that exhibited reasonable pharmacokinetic stability and showed moderate in vivo activity against a variety of tumor cell lines. The analogous C-11 single compound, pyridylacetamide 2, was found to be more potent than 1 in FPT inhibition. Further studies showed that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a single bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-substituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic profile with AUC of 84.9 and t1/2 of 82 min. Compound4 inhibited the growth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.

Published
1998

2. Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4- (8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene )- piperidine inhibitors of farnesyl-protein transferase: design and synthesis of in vivo active antitumor compounds

Author

Bohdan Yaremko, Ashit K. Ganguly, D. F. Rane, M. Malkowski, Robert Patton, Chin-Chung Lin, Walter R. Bishop, Bancha Vibulbhan, Jianping Chen, Amin A. Nomeir, Philip Lipari, Doll Ronald J, Matthew Bryant, Joanne M. Petrin, Chen Kj, Dell J, Ming Liu, Z. Li, F. G. Njoroge, Girijavallabhan, I. King, Suining Lee, and Joseph J. Catino

Subjects
Magnetic Resonance Spectroscopy, Farnesyl Protein Transferase, medicine.drug_class, Stereochemistry, Pyridines, Substituent, Protein Prenylation, Mice, Nude, Carboxamide, Antineoplastic Agents, Transfection, Chemical synthesis, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Piperidines, Drug Discovery, medicine, Structure–activity relationship, Phenyl group, Animals, Enzyme Inhibitors, Alkyl and Aryl Transferases, biology, Molecular Structure, 3T3 Cells, Neoplasms, Experimental, chemistry, Enzyme inhibitor, Drug Design, COS Cells, biology.protein, ras Proteins, Molecular Medicine, Piperidine
Abstract

Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.

Published
1998

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