Exploring the role of bromine at C(10) of (+)-4-[2-[4-(8-chloro-3,10-dibromo- 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2- oxoethyl]-1-piperidinecarboxamide (Sch-66336): the discovery of indolocycloheptapyridine inhibitors of farnesyl protein transferase.

Article Details

Citation Copy to clipboard

Taveras AG, Aki C, Chao J, Doll RJ, Lalwani T, Girijavallabhan V, Strickland CL, Windsor WT, Weber P, Hollinger F, Snow M, Patton R, Kirschmeier P, James L, Liu M, Nomeir A

J Med Chem. 2002 Aug 29;45(18):3854-64.

PubMed ID

12190309 [ View in PubMed

]

Abstract

The 10-bromobenzocycloheptapyridyl farnesyl transferase inhibitor (FTI) Sch-66336 (1) is currently under clinical evaluation for the treatment of human cancers. During structure-activity relationship development leading to 1, 10-bromobenzocycloheptapyridyl FTIs were found to be more potent than analogous compounds lacking the 10-Br substituent. This potency enhancement was believed to be due, in part, to an increase in conformational rigidity as the 10-bromo substituent could restrict the conformation of the appended C(11) piperidyl substituent in an axial orientation. A novel and potent class of FTIs, represented by indolocycloheptapyridine Sch-207758 [(+)-10a], have been designed based on this principle. Although structural and thermodynamic results suggest that entropy plays a crucial role in the increased potency observed with (+)-10a through conformational constraints and solvation effects, the results also indicate that the indolocycloheptapyridine moiety in (+)-10a provides increased hydrophobic interactions with the protein through the addition of the indole group. This report details the X-ray structure and the thermodynamic and pharmacokinetic profiles of (+)-10a, as well as the synthesis of indolocycloheptapyridine FTIs and their potencies in biochemical and biological assays.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Lonafarnib	Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	IC 50 (nM)	1.9	N/A	N/A	Details