Bridgehead modification of trihalocycloheptabenzopyridine leads to a potent farnesyl protein transferase inhibitor with improved oral metabolic stability.

Article Details

Citation

Njoroge FG, Vibulbhan B, Shi X, Strickland C, Kirschmeier P, Bishop R, Nomeir A, Girijavallabhan V

Bridgehead modification of trihalocycloheptabenzopyridine leads to a potent farnesyl protein transferase inhibitor with improved oral metabolic stability.

Bioorg Med Chem Lett. 2004 Dec 6;14(23):5899-902.

PubMed ID
15501065 [ View in PubMed
]
Abstract

Modification of the ethano bridge of the core structure of the antitumor agent, SARASAR (SCH66336) with concomitant introduction of a sulfonamide moiety off the distal piperidine afforded inhibitor 9-(S-), a compound with greatly improved PK profile. Other compounds with enhanced FPTase inhibitory activity were obtained as exemplified by amide 10-(S-) and urea 11-(S-): these compounds demonstrated activity in picomolar range.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
LonafarnibProtein farnesyltransferase/geranylgeranyltransferase type-1 subunit alphaIC 50 (nM)2N/AN/ADetails
LonafarnibProtein farnesyltransferase/geranylgeranyltransferase type-1 subunit alphaIC 50 (nM)500000N/AN/ADetails