Hunt J T, Lee V G, Leftheris K, Seizinger B, Carboni J, Mabus J, Ricca C, Yan N, Manne V
Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
J Med Chem. 1996 Jan 19;39(2):353-8. doi: 10.1021/jm9507284.
All previously reported CAAX-based farnesyltransferase inhibitors contain a thiol functionality. We report that attachment of the 4-imidazolyl group, via 1-, 2-, or 3-carbon alkyl or alkanoyl spacers, to Val-Tic-Met or tLeu-Tic-Gln provides potent FT inhibitors. (R*)-N-[[1,2,3,4-Tetrahydro-2-[N-[2-(1H-imidazol-4-yl)ethyl] -L-valyl]-3-isoquinolinyl]carbonyl]-L-methionine ([imidazol- 4-yl-ethyl]-Val-Tic-Met), with FT IC50 = 0.79 nM, displayed potent cell activity in the absence of prodrug formation (SAG EC50 = 3.8 muM).
所有先前报道的基于CAAX的法尼基转移酶抑制剂都含有硫醇官能团。我们报道，通过1-、2-或3-碳烷基或烷酰基间隔基将4-咪唑基连接到Val-Tic-Met或tLeu-Tic-Gln上可提供有效的法尼基转移酶（FT）抑制剂。(R*)-N-[[1,2,3,4-四氢-2-[N-[2-(1H-咪唑-4-基)乙基]-L-缬氨酰基]-3-异喹啉基]羰基]-L-甲硫氨酸（[咪唑-4-基-乙基]-Val-Tic-Met），其FT IC50 = 0.79 nM，在不形成前药的情况下表现出强大的细胞活性（SAG EC50 = 3.8 μM）。
