Potent, selective, and orally bioavailable tricyclic pyridyl acetamide N-oxide inhibitors of farnesyl protein transferase with enhanced in vivo antitumor activity

F G Njoroge; B Vibulbhan; P Pinto; W R Bishop; M S Bryant; A A Nomeir; C Lin; M Liu; R J Doll; V Girijavallabhan; A K Ganguly

doi:10.1021/jm980013b

Potent, selective, and orally bioavailable tricyclic pyridyl acetamide N-oxide inhibitors of farnesyl protein transferase with enhanced in vivo antitumor activity

J Med Chem. 1998 May 7;41(10):1561-7. doi: 10.1021/jm980013b.

Authors

F G Njoroge¹, B Vibulbhan, P Pinto, W R Bishop, M S Bryant, A A Nomeir, C Lin, M Liu, R J Doll, V Girijavallabhan, A K Ganguly

Affiliation

¹ Schering-Plough Research Institute, Departments of Chemistry and Tumor Biology, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.

PMID: 9572881
DOI: 10.1021/jm980013b

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.

MeSH terms

Administration, Oral
Alkyl and Aryl Transferases / antagonists & inhibitors*
Animals
Antineoplastic Agents* / administration & dosage
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / pharmacokinetics
Antineoplastic Agents* / pharmacology
Biological Availability
Cyclic N-Oxides* / administration & dosage
Cyclic N-Oxides* / chemical synthesis
Cyclic N-Oxides* / pharmacokinetics
Cyclic N-Oxides* / pharmacology
Drug Screening Assays, Antitumor
Enzyme Inhibitors* / administration & dosage
Enzyme Inhibitors* / chemical synthesis
Enzyme Inhibitors* / pharmacokinetics
Enzyme Inhibitors* / pharmacology
Female
Humans
Mice
Mice, Nude
Neoplasm Transplantation
Oncogene Protein p21(ras) / antagonists & inhibitors
Pyridines* / administration & dosage
Pyridines* / chemical synthesis
Pyridines* / pharmacokinetics
Pyridines* / pharmacology
Tumor Cells, Cultured

Substances

4-(3-bromo-8-chloro-11H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-yl)-1-((4-pyridinyl)acetyl)piperidine N1-oxide
4-(8-chloro-3,5-dibromo-11H-benzo(5,6)-cyclohepta(1,2-b)pyridin-11-yl)-1-((4-pyridinyl)acetyl)piperidine N1-oxide
4-(bromo-8-chloro-6,11-dihydro-5H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-yl)-1-((4-pyridinyl)acetyl)piperidine N1-oxide
Antineoplastic Agents
Cyclic N-Oxides
Enzyme Inhibitors
Pyridines
Alkyl and Aryl Transferases
p21(ras) farnesyl-protein transferase
Oncogene Protein p21(ras)