Inhibitors of farnesyl protein transferase. Synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system

R Wolin; M Connolly; J Kelly; J Weinstein; S Rosenblum; A Afonso; L James; P Kirschmeier; W R Bishop

doi:10.1016/s0960-894x(98)00439-9

Inhibitors of farnesyl protein transferase. Synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system

Bioorg Med Chem Lett. 1998 Sep 22;8(18):2521-6. doi: 10.1016/s0960-894x(98)00439-9.

Authors

R Wolin¹, M Connolly, J Kelly, J Weinstein, S Rosenblum, A Afonso, L James, P Kirschmeier, W R Bishop

Affiliation

¹ Schering-Plough Research Institute, Department of Chemistry, Kenilworth, New Jersey 07033, USA.

PMID: 9873573
DOI: 10.1016/s0960-894x(98)00439-9

Abstract

Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol.

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Amides / chemistry*
Benzazepines / chemistry
Benzoxepins / chemistry
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Guanidines / chemistry*
Models, Chemical
Piperazines / chemistry
Piperidines / chemistry
Protein Prenylation / drug effects*
Pyridines / chemistry
Structure-Activity Relationship

Substances

Amides
Benzazepines
Benzoxepins
Enzyme Inhibitors
Guanidines
Piperazines
Piperidines
Pyridines
Alkyl and Aryl Transferases
p21(ras) farnesyl-protein transferase
dicyandiamido