From Random Screening of Chemical Libraries to the Optimization of FPP-Competitive Inhibitors of Farnesyltransferase

Mailliet, Patrick; Laoui, Abdel; Bourzat, Jean‐Dominique; Capet, Marc; Chevé, Michel; Commerçon, Alain; Dereu, N.; LeBrun, Alain; Martin, Jean‐Paul Saint; Peyronel, Jean‐Francois; Salagnad, Christophe; Thompson, Fabienne; Zucco, Martine; Guitton, Jean-Dominique; Pantel, Guy; Bissery, Marie-Christine; Brealey, Clive; Lavayre, Jacques; Lelièvre, Yves; Riou, Jean‐François; Vrignaud, Patricia; Duchesne, Marc; Lavelle, François

doi:10.1385/1-59259-013-6:115

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“…A major obstacle related to this strategy is the lack of selectivity of inhibitors for FT over geranylgeranyltransferase (GGT). Among the numerous series of compounds optimized toward an acceptable selectivity, the benzo[ f ]perhydroisoindole (BPHI) class (studied by Aventis) is one of the most efficient in vitro . Compounds such as RPR 115135 ( 1 ; Figure ) show acceptable cellular potency with moderate in vivo activity.…”

Section: Introductionmentioning

confidence: 99%

Diastereoselective Syntheses of New Analogues of the Farnesyltransferase Inhibitor RPR 130401

et al. 2004

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The access to several benzo[f]perhydroisoindolic analogues of farnesyltransferase inhibitors from a single dienic precursor is reported. An initial [4 + 2] cycloaddition between diphenylisobenzofuran6 and pyrrolines 11, 14, and 15 led to either the syn or the anti isomers, depending on the mode of activation of the cycloaddition. The syn diastereomers were isolated in 90% de under 12 kbar at room temperature, while their anti counterparts were obtained with the same selectivity by warming the reaction mixture to 110 degrees C in toluene at atmospheric pressure. Both syn and anti adducts were separately N-deprotected, and the resulting amines reacted with an activated ester derived from the acid (20) to afford the final targets (5). Two new analogues (5a and 5b) of the FT inhibitor RPR 130401 were thus synthesized in a mere three-step synthetic scheme with overall yields from 30 to 60%.

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Section: Introductionmentioning

confidence: 99%