A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC(50)), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC(50)), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.
Efficient and practical access to chiral aminocyclopropanes is secured by the title reaction (see example). Both E and Z enamides undergo the cyclopropanation with high diastereoselectivity (d.r. up to >95:5). The application of this methodology to the synthesis of biologically significant aminocyclopropanes illustrates the potential of chiral enamides as useful building blocks for stereoselective organic synthesis.
A detailed account on Simmons-Smith cyclopropanations of allenamides en route to amido-spiro[2.2]pentanes is described here. While the diastereoselectivity was low when using unsubstituted allenamides, the reaction is overall efficient and general, representing the most direct synthesis of both chemically and biologically interesting amido-spiro[2.2]pentane systems. With α-substituted allenamides, while the diastereoselectivity could be improved significantly based on a series of conformational analysis, both mono- and bis-cyclopropanation products were observed. Consequently, several structurally intriguing amido-methylene cyclopropanes could also be prepared.
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