Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

Abstract

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.

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

“…Preclinical pharmacokinetic studies in mice have shown that orally administered SB939 (50 mg/kg; single dose) reaches a higher maximum concentration (C max ), with higher oral bioavailability (F%) and a longer half-life (t 1/2 ), than that of SAHA (Table 1). In vitro safety pharmacology data also show that SB939 (10 M) does not interfere with the activity of non-HDAC enzymes, including other Zn 2ϩ -dependent enzymes, G-protein-coupled receptors, monoamine transporters, and ion channels (47,65). SB939 thus has a promising profile as a new HDAC inhibitor.…”

“…Here we investigated the antimalarial activity of a new hydroxamate-based HDAC inhibitor that is currently in phase I clinical trials for the treatment of cancer (52,67). SB939 was developed from a medicinal chemistry program focused on addressing the general lack of metabolic stability and poor in vivo pharmacokinetics displayed by HDAC inhibitors (65). From a medicinal chemistry point of view, SB939 obeys Lipinski's rule of five (39) and has the appropriate size, hydrophobicity, and polar surface parameters (e.g., molecular weight ϭ 358, octanol-water partition coefficient [clogP] ϭ 3.2, number of H-bond donors ϭ 2, number of H-bond acceptors ϭ 6, and total polar surface area [TPSA] ϭ 68%) required for oral bioavailability.…”

“…In this study, we tested the in vitro and in vivo antiplasmodial efficacies of a new, orally bioavailable, hydroxamate-based HDAC inhibitor undergoing clinical trials for cancer (35,47,52,65,67). SB939 (pracinostat; S*BIO), a pan-HDAC inhibitor acting on class I, II, and IV HDACs (47,65), has a longer in vivo half-life (t 1/2 of 2.4 h) than those of other hydroxamate-based HDAC inhibitors, such as SAHA (t 1/2 of 0.75 h) ( Table 1).…”

“…SB939 (pracinostat; S*BIO), a pan-HDAC inhibitor acting on class I, II, and IV HDACs (47,65), has a longer in vivo half-life (t 1/2 of 2.4 h) than those of other hydroxamate-based HDAC inhibitors, such as SAHA (t 1/2 of 0.75 h) ( Table 1). Here we present data on the first reported noncancer application of this compound.…”

Palladium-Catalyzed Intermolecular Oxidative Amination of Alkenes with Amines, Using Molecular Oxygen as Terminal Oxidant

“…Nitrogen-containing compounds are ubiquitous in nature, and many are important organic compounds with applications as medicines, dyes, and electroluminescent materials [1][2][3]. The development of synthetic methods for nitrogen-containing compounds is therefore an important topic.…”