Structure−Activity Relationship of 3-Substituted N-(Pyridinylacetyl)-4- (8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)- piperidine Inhibitors of Farnesyl-Protein Transferase:  Design and Synthesis of in Vivo Active Antitumor Compounds

Abstract

Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.

Farnesyltransferase Inhibitors Reverse Taxane Resistance

“…To investigate whether the FTI-induced enhancement of Flutax-2 binding on the microtubule is dependent on the inhibition of farnesyltransferase activity, we used the inactive lonafarnib enantiomer, SCH66337. This enantiomer is at least 100-fold less active than lonafarnib against farnesyltransferase in vitro and has practically no effect in cell systems (23). We first confirmed the lack of antifarnesyltransferase activity of SCH66337 by monitoring the drug-induced inhibition of protein farnesylation (HDJ-2 in this case) over time (Fig.…”

Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia

“…26,31 This compound has been described in detail elsewhere. [32][33][34] SCH66336 was received in lyophilized form, reconstituted in dimethyl sulfoxide (DMSO), and maintained at Ϫ20°C. For experiments in tissue culture, SCH66336 was diluted at least 1:500 in appropriate tissue culture media before it was added to in vitro assays.…”

A farnesyl transferase inhibitor suppresses TPA-mediated skin tumor development without altering hyperplasia in the ras transgenic Tg.AC mouse

“…SCH56582, a tricyclic FTI [20], was obtained from Schering-Plough Research Institute and dissolved in 5% dimethylsulfoxide (DMSO)/acetone (5:95, v/v), or acetone alone, at a concentration of 2.544 mg/mL and delivered in a volume of 200 mL (0.509 mg per dose).…”