STRUCTURE-ACTIVITY RELATIONSHIP OF 3-SUBSTITUTED ,6]CYCLOHEPTA[1,2-B]PYRIDIN-11-YLIDENE)-PIPERIDINE INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE - DESIGN AND SYNTHESIS OF IN-VIVO ACTIVE ANTITUMOR COMPOUNDS

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 tricy clic 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 b ulky 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 ac tive. Whereas compound SCH 44342 did not show appreciable in vivo anti tumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when a dministered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are no npeptidic and do not contain sulfhydryl groups. They selectively inhib it FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They als o inhibit H-Ras processing in COS monkey kidney cells and soft agar gr owth of Ras-transformed cells.