Benzopyran sulfonamides as KV1.5 potassium channel blockers

K(V)1.5 blockers have the potential to be atrium-selective agents for treatment of atrial fibrillation. The benzopyrans provide a template for the synthesis of potent and selective K(V)1.5 blockers.     

Inhibitors of potassium channels KV1.3 and IK-1 as immunosuppressants

New structural classes of K_V1.3 and IK-1 ion channel blockers have been identified based on a virtual high throughput screening approach using a homology model of KcsA. These compounds display inhibitory effects on T-cell and/or keratinocyte proliferation and immunosuppressant activity within a DTH animal model.     

Hypoxia suppresses KV1.5 channel expression through endogenous 15-HETE in rat pulmonary artery

Hypoxia initiated pulmonary vasoconstriction is due to the inhibition of voltage-gated K(+) (K(V)) channels. But the mechanism is unclear. We have evidence that hypoxia activates 15-lipoxygenase (15-LOX) in distal pulmonary arteries and increases the formation of 15-hydroxyeicosatetraenoate (15-HETE). 15-HETE-induced pulmonary artery constriction to be through the inhibition of K(V) channels (K(V)1.5, K(V)2.1 and K(V)3.4). However, no direct link among hypoxia, 15-HETE and inhibition of K(V) subtypes is established. Therefore, we investigated whether 15-LOX/15-HETE pathway contributes to the hypoxia-induced down-regulation of K(V) channels. As K(V)1.5 channel is O(2)-sensitive, it was chosen in the initial study. We found that inhibition of 15-LOX suppressed the response of hypoxic pulmonary artery rings to phenylephrine. The expressions of K(V)1.5 channel mRNA and protein was robustly up-regulated in cultured PASMC and pulmonary artery after blocking of 15-LOX by lipoxygenase inhibitors in hypoxia. The 15-LOX blockade also partly rescued the voltage-gated K(+) current (I(K(V))). 15-HETE contributes to the down-regulation of K(V)1.5 channel, inhibition of I(K(V)) and increase of native pulmonary artery tension after hypoxia. Hypoxia inhibits K(V)1.5 channel through 15-LOX/15-HETE pathway.     

Inhibitors of lipoprotein(a) assembly

Compounds of the general structure A and B were investigated for their activity as lipoprotein(a), [Lp(a)], assembly (coupling) inhibitors. SAR around the amino acid derivatives (structure A) gave compound 14-6 as a potent coupling inhibitor. Oral dosing of compound 14-6 to Lp(a) transgenic mice and cymologous monkeys resulted in a>30% decrease in plasma Lp(a) levels after 1-2 weeks of treatment at 100 mg/kg/day.     

Role of Voltage-Gated K+ (KV) Channels in Vascular Function

Voltage-dependent K⁺ (K_V) channels represent the most diverse group of K⁺ channels ubiquitously expressed in vascular smooth muscles. The K_V channels, together with other types of K⁺ conductances, such as Ca²⁺-activated (BK_Ca), ATP-sensitive (K_ATP), and inward rectifier, play an important role in the control of the cell membrane potential and regulation of the vascular contractility. Comparison of the expression of different K_V channel isoforms obtained from RT-PCR studies showed that virtually all K_V genes could be detected in vascular smooth muscle cells (VSMC). Based on the analysis of both mRNA and protein expressions, it is likely that K_V1.1, K_V1.2, K_V1.3, K_V1.5, K_V1.6, K_V2.1, and K_V3.1b channel isoforms are mainly responsible for the delayed rectifier current characterized electrophysiologically in most VSMC types studied to date. It has been recently demonstrated by our research group and by others that functional expression of multiple K_V channel α-subunits is not homogeneous and varies in different vascular beds of small and large arteries. Growing evidence suggests that in some small arteries, e.g., cerebral arteries and arterioles, the K_V channels are activated at more negative membrane voltages than BK_Ca, thus making a greater contribution to the control of vascular tone. Our data also suggest that in some blood vessels, such as the rat aorta and mouse small mesenteric arteries, the K_V channel current (identified mainly as passed through K_V2.1 channels), but not BK_Ca, is the predominant conductance activated even under conditions where intracellular Ca₂₊ concentration is increased up to 200 nM. In addition, our data indicate that the K_V2.1 channel current could also contribute to the regulation of the induced rhythmic activity in the rat aorta in vitro acting as a negative feedback mechanism for membrane depolarization. We and other experimenters also demonstrated that functional expression of K_V channels is a dynamic process, which is altered under normal physiological conditions (e.g., during the development of the vessels), and in various pathological states (e.g., pulmonary hypertension developing during chronic hypoxia). Recent findings also suggest that activation of K_V channels can also play a role in vascular apoptosis (causing loss of intracellular K⁺ and subsequent cell shrinking, one of the essential prerequisites of cellular apoptosis). To summarize, the K^V channels are essential for normal vascular function, and their expression and properties are altered under abnormal conditions. Therefore, understanding of the molecular identity of native K_V channels and their functional significance and elucidation of the mechanisms, which govern and control the expression of the K_V channels in the vasculature, represent an important and challenging task and could also lead to the development of useful therapeutic strategies for the treatment of cardiovascular diseases.     

Nucleoside and Nucleotide Inhibitors of Inosine Monophosphate (IMP) Dehydrogenase as Potential Antitumor Inhibitors

Abstract

A review of various nucleoside and nucleotide inhibitors of IMP dehydrogenase suggests that such inhibitors may also exhibit significant antitumor effects. The details of the precise mode of action and structure activity relationships remain to be established. This new area of research should prove fruitful for uncovering useful and more specific antitumor agents.     

Protein Glycation Inhibitors from Thyme (Thymus vulgaris)

Nonenzymatic glycation of bovine serum albumin (BSA) was inhibited in vitro by some extracts of 34 kinds of spices. The methanol extract of thyme (Thymus vulgaris) had the most potent inhibitory activity among them. Chromatographic purification yielded four flavonoids, quercetin (1), eriodictyol (2), 5,6,4´-trihydroxy-7,8,3´-trimethoxyflavone (3), and cirsilineol (4). These known flavonoids suppressed the levels of advanced glycation end products (AGEs) and fructosamines, shown by the measurement of specific fluorescent groups and the reduction of nitroblue tetrazolium (NBT), respectively. The inhibitory activities were compared with those of other structure-related flavonoids and aminoguanidine.     

Electron spin-lattice relaxation of the [Cu(1.5) ... Cu(1.5)] dinuclear copper center in nitrous oxide reductase.

Relaxation times have been obtained with time-domain EPR for the dinuclear mixed valence [CuA(1.5) ... CuA(1.5)[ S = 1/2 center in nitrous oxide reductase, N2OR, from Pseudomonas stutzeri, in the TN5 mutant defective in copper chromophore biosynthesis, in a synthetic mixed valence complex, and in type 1 and 2 copper complexes. Data confirmed that the intrinsic electron spin-lattice relaxation time, T1, for N2OR in the temperature range of 6-25 K is unusually short for copper centers. At best, a twofold increase of T1 from g perpendicular to g parallel was measured. Optimized fits of the saturation-recovery data were obtained using both double-exponential and stretched-exponential functions. The temperature dependence of the spin-lattice relaxation rate of mutant N2OR is about T5.0 with the stretched-exponential model or T3.3 and T3.9 for the model using the sum of two exponentials. These T1s are intrinsic to the mixed valence [CuA(1.5) ... CuA(1.5)] center, and no interaction of the second copper center in wild-type N2OR with the [CuA(1.5) ... CuA(1.5)] center has been observed. The T1 of the mixed valence center of N2OR is not only shorter than for monomeric square planar Cu(II) complexes, but also shorter than for a synthetic mixed valence complex, Cu2(N[CH2CH2NHCH2CH2NHCH2CH2]3N). The short T1 is attributed to the vibrational modes of type 1 copper and/or the metal-metal interaction in [CuA(1.5) ... CuA(1.5)].     

Effective Cytochrome P450 (CYP) Inhibitors Isolated from Tarragon (Artemisia dracunculus)

Two effective cytochrome P450 (CYP) inhibitors were isolated from tarragon, Artemisia dracunculus. Their structures were spectroscopically identified as 2E,4E-undeca-2,4-diene-8,10-diynoic acid isobutylamide (1) and 2E,4E-undeca-2,4-diene-8,10-diynoic acid piperidide (2). Both compounds had dose-dependent inhibitory effects on CYP3A4 activity with IC₅₀ values of 10.0 ± 1.3 µM for compound 1 and 3.3 ± 0.2 µM for compound 2, and exhibited mechanism-based inhibition. This is the first reported isolation of effective CYP inhibitors from tarragon (Artemisia dracunculus) purchased from a Japanese market.     

A (1.5 + epsilon)-approximation algorithm for unsigned translocation distance

Genome rearrangement is an important area in computational biology and bioinformatics. The translocation operation is one of the popular operations for genome rearrangement. It was proved that computing the unsigned translocation distance is NP-hard. In this paper, we present a (1.5 + epsilon)-approximation algorithm for computing unsigned translocation distance which improves upon the best known 1.75-ratio. The running time of our algorithm is O(n2 + (4/epsilon)1.5 square root log(4/epsilon )2(4/epsilon), where n is the total number of genes in the genome.     

Acetyl-CoA Carboxylase Inhibitors from Avocado (Persea americana Mill) Fruits

A methanol extract of avocado fruits showed potent inhibitory activity against acetyl-CoA carboxylase, a key enzyme in fatty acid biosynthesis. The active principles were isolated and identified as (5E,12Z,15Z)-2-hydroxy-4-oxoheneicosa-5,12,15-trienyl (1), (2R,12Z,15Z)-2-hydroxy-4-oxoheneicosa-12,15-dienyl (2), (2R^*,4R^*)-2,4-dihydroxyheptadec-16-enyl (3) and (2R^*,4R^*)-2,4-dihydroxyheptadec-16-ynyl (4) acetates by instrumental analyses. The IC₅₀ of the compounds were 4.0×10^-6, 4.9×10^-6, 9.4×10^-6, and 5.1×10^-6M, respectively.     

Cholesteryl Ester Transfer Protein (CETP) Deficiency and CETP Inhibitors

Epidemiologic studies have shown that low-density lipoprotein cholesterol (LDL-C) is a strong risk factor, whilst high-density lipoprotein cholesterol (HDL-C) reduces the risk of coronary heart disease (CHD). Therefore, strategies to manage dyslipidemia in an effort to prevent or treat CHD have primarily attempted at decreasing LDL-C and raising HDL-C levels. Cholesteryl ester transfer protein (CETP) mediates the exchange of cholesteryl ester for triglycerides between HDL and VLDL and LDL. We have published the first report indicating that a group of Japanese patients who were lacking CETP had extremely high HDL-C levels, low LDL-C levels and a low incidence of CHD. Animal studies, as well as clinical and epidemiologic evidences, have suggested that inhibition of CETP provides an effective strategy to raise HDL-C and reduce LDL-C levels. Four CETP inhibitors have substantially increased HDL-C levels in dyslipidemic patients. This review will discuss the current status and future prospects of CETP inhibitors in the treatment of CHD. At present anacetrapib by Merck and evacetrapib by Eli Lilly are under development. By 100mg of anacetrapib HDL-C increased by 138%, and LDL-C decreased by 40%. Evacetrapib 500 mg also showed dramatic 132% increase of HDL-C, while LDL-C decreased by 40%. If larger, long-term, randomized, clinical end point trials could corroborate other findings in reducing atherosclerosis, CETP inhibitors could have a significant impact in the management of dyslipidemic CHD patients. Inhibition of CETP synthesis by antisense oligonucleotide or small molecules will produce more similar conditions to human CETP deficiency and may be effective in reducing atherosclerosis and cardiovascular events. We are expecting the final data of prospective clinical trials by CETP inhibitors in 2015.     

Inhibitors of multidrug resistance (MDR) have affinity for MDR substrates

Multidrug-resistance (MDR) occurs in many bacterial species and tumour cells. MDR functions by membrane proteins which export drugs from cells, resulting in a low ineffective concentration of the drug. We have shown by molecular modelling that inhibitors of MDR have affinity for substrates of MDR transporters. This affinity may facilitate drug entry into cells and a large inhibitor-drug complex may be a poorer substrate for the MDR mechanism. This complex would effectively 'cloak' the drug rendering it unavailable for efflux.     

Inhibitors of proteolytic enzymes under abiotic stresses in plants (review)

Data on the role of proteolytic enzyme inhibitors in plant adaptation to various unfavorable environmental abiotic factors--water deficiency, salinization of soil, extreme temperatures, etc.--and also probable functions of proteinases inhibitors in natural plant senescense are considered.     

Delayed-rectifier (KV2.1) regulation of pancreatic beta-cell calcium responses to glucose: inhibitor specificity and modeling

The delayed-rectifier (voltage-activated) K(+) conductance (K(V)) in pancreatic islet beta-cells has been proposed to regulate plasma membrane repolarization during responses to glucose, thereby determining bursting and Ca(2+) oscillations. Here, we verified the expression of K(V)2.1 channel protein in mouse and human islets of Langerhans. We then probed the function of K(V)2.1 channels in islet glucose responses by comparing the effect of hanatoxin (HaTx), a specific blocker of K(V)2.1 channels, with a nonspecific K(+) channel blocker, tetraethylammonium (TEA). Application of HaTx (1 microM) blocked delayed-rectifier currents in mouse beta-cells, resulting in a 40-mV rightward shift in threshold of activation of the voltage-dependent outward current. In the presence of HaTx, there was negligible voltage-activated outward current below 0 mV, suggesting that K(V)2.1 channels form the predominant part of this current in the physiologically relevant range. We then employed HaTx to study the role of K(V)2.1 in the beta-cell Ca(2+) responses to elevated glucose in comparison with TEA. Only HaTx was able to induce slow intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations in cells stimulated with 20 mM glucose, whereas TEA induced an immediate rise in [Ca(2+)](i) followed by rapid oscillations. In human islets, HaTx acted in a similar fashion. The data were analyzed using a detailed mathematical model of ionic flux and Ca(2+) regulation in beta-cells. The results can be explained by a specific HaTx effect on the K(V) current, whereas TEA affects multiple K(+) conductances. The results underscore the importance of K(V)2.1 channel in repolarization of the pancreatic beta-cell plasma membrane and its role in regulating insulin secretion.