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γ-Butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to l-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids. BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate (mildronate), which is an approved, clinically used cardioprotective drug, is a relatively poor BBOX inhibitor and requires high daily doses. In this paper we describe the design, synthesis, and properties of 51 compounds, which include both GBB and mildronate analogues. We have discovered novel BBOX inhibitors with improved IC50 values; the best examples are in the nanomolar range and about 2 orders of magnitude better when compared to mildronate. For six inhibitors, crystal structures in complex with BBOX have been solved to explain their activities and pave the way for further inhibitor design.

BACKGROUND AND PURPOSEThe important pathological consequences of ischaemic heart disease arise from the detrimental effects of the accumulation of long-chain acylcarnitines in the case of acute ischaemia-reperfusion. The aim of this study is to test whether decreasing the L-carnitine content represents an effective strategy to decrease accumulation of long-chain acylcarnitines and to reduce fatty acid oxidation in order to protect the heart against acute ischaemia-reperfusion injury. KEY RESULTSIn this study, we used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (Methyl-GBB), which inhibits γ-butyrobetaine dioxygenase (IC50 3 μM) and organic cation transporter 2 (OCTN2, IC50 3 μM), and, in turn, decreases levels of L-carnitine and acylcarnitines in heart tissue. Methyl-GBB reduced both mitochondrial and peroxisomal palmitate oxidation rates by 44 and 53% respectively. In isolated hearts treated with Methyl-GBB, uptake and oxidation rates of labelled palmitate were decreased by 40%, while glucose oxidation was increased twofold. Methyl-GBB (5 or 20 mg·kg ) attenuated the infarct size by 45% and improved 24 h survival of rats by 20-30%. CONCLUSIONS AND IMPLICATIONSReduction of L-carnitine and long-chain acylcarnitine content by the inhibition of OCTN2 represents an effective strategy to protect the heart against ischaemia-reperfusion-induced damage. Methyl-GBB treatment exerted cardioprotective effects and increased survival by limiting long-chain fatty acid oxidation and facilitating glucose metabolism. AbbreviationsAAR, area at risk; ACOX, acyl-CoA oxidase 1; ACSL, long-chain fatty acid CoA synthetase; AN, area of necrosis; BBOX, γ-butyrobetaine dioxygenase; CD36, fatty acid translocase; CPT I, carnitine palmitoyltransferase I; FABP, fatty acid binding protein; FAO, fatty acid oxidation; HR, heart rate; IHD, ischaemic heart disease; IS, infarct size; KH, Krebs-Henseleit; LAD, left anterior descending coronary artery; LCFA, long-chain fatty acids; LV, left ventricle; LVDP, left ventricle developed pressure; IntroductionIschaemic heart disease (IHD) is a major medical problem causing disability and death for millions of people annually (Lavie et al., 2009). The important pathological consequences of IHD arise from the detrimental effects of the accumulation of long-chain fatty acids (LCFAs) in the case of acute ischaemia-reperfusion (Wang and Lopaschuk, 2007;Liepinsh et al., 2013b). Therefore, pharmacological intervention that targets LCFA accumulation has been suggested for the development of novel treatment strategies to improve the clinical outcomes of patients with IHD (Horowitz et al., 2010;Lopaschuk et al., 2010). The main advantages of reduced LCFA oxidation are the reduction of energy waste through mitochondrial uncoupling induced by LCFA overload as well as the reduction of direct damage by LCFA metabolites on glucose metabolism and insulin signalling (Zhang et al., 2011). In addition, pharmacological manipulation of energy metabolism does not directly influence the haemodynamic parameters of th...

Dedicated to Professor Rolf Huisgen on the occasion of his 85th birthday Inhibition of the enzyme histone deacetylase (HDAC) is emerging as a novel approach to the treatment of cancer. A series of novel sulfonamide derivatives were synthesized and evaluated for their ability to inhibit human HDAC. Compounds were identified which are potent enzyme inhibitors, with IC 50 values in the low nanomolar range against enzyme obtained from HeLa cell extracts, and with antiproliferative effects in cell culture. Extensive characterization of the structure ± activity relationships of this series identified key requirements for activity. These include the direction of the sulfonamide bond and substitution patterns on the central phenyl ring. The alkyl spacer between the aromatic head group and the sulfonamide functionality also influenced the HDAC inhibitory activity. One of these compounds, m11.1, also designated PXD101, has entered clinical trials for solid tumors and haematological malignancies.