Potent, Selective, and Orally Bioavailable Tricyclic Pyridyl Acetamide N-Oxide Inhibitors of Farnesyl Protein Transferase with Enhanced in Vivo Antitumor Activity
| Autor: | 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, V. Girijavallabhan |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
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 |
| Zdroj: | Journal of Medicinal Chemistry. 41:1561-1567 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm980013b |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|