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

Journal of Medicinal Chemistry
F George NjorogeA K Ganguly

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...Continue Reading

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Citations

Jan 4, 2003·Archives of Pharmacal Research·Joonghup KimJin-Hyun Jeong
May 18, 1999·Bioorganic & Medicinal Chemistry Letters·D J AugeriS H Rosenberg
Sep 5, 2006·Cancer Research·Adam I MarcusParaskevi Giannakakou
Sep 23, 2008·Bioorganic & Medicinal Chemistry Letters·Julian BlaggKevin Beaumont
Feb 22, 2021·European Journal of Medicinal Chemistry·Shuo YuanBin Yu
Jun 17, 1999·Annals of Oncology : Official Journal of the European Society for Medical Oncology·T PetitD D Von Hoff
Sep 28, 2000·Cancer Treatment Reviews·F A EskensJ Verweij
Oct 23, 1998·Journal of Medicinal Chemistry·D J AugeriS Rosenberg
May 26, 2005·Journal of the American Chemical Society·Ryoichi TanakaHirokazu Urabe

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