Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor γt (RORγt) Agonist Structure-Based Functionality Switching Approach from In House RORγt Inverse Agonist to RORγt Agonist.

Retinoic acid receptor-related orphan receptor γt (RORγt) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation of Th17 cells and Tc17 cells. Herein, we describe a novel structure-based functionality switching approach from in house well-optimized RORγt inverse agonists to potent RORγt agonists. We succeeded in the identification of potent RORγt agonist 5 without major chemical structure change. The biochemical response was validated by molecular dynamics simulation studies that showed a helix 12 stabilization effect of RORγt agonists. These results indicate that targeting helix 12 is an attractive and novel medicinal chemistry strategy for switching existing RORγt inverse agonists to agonists.

Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders.

It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3',5'-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.

Parallel fluorescent probe synthesis based on the large-scale preparation of BODIPY FL propionic acid.

We describe a methodology for quick development of fluorescent probes with the desired potency for the target of interest by using a method of parallel synthesis, termed as Parallel Fluorescent Probe Synthesis (Parallel-FPS). BODIPY FL propionic acid 1 is a widely used fluorophore, but it is difficult to prepare a large amount of 1, which hinders its use in parallel synthesis. Optimization of a synthetic scheme enabled us to obtain 50g of 1 in one batch. With this large quantity of 1 in hand, we performed Parallel-FPS of BODIPY FL-labeled ligands for estrogen related receptor-α (ERRα). An initial trial of the parallel synthesis with various linkers provided a potent ligand for ERRα (Reporter IC50=80nM), demonstrating the usefulness of Parallel-FPS.

Fasiglifam (TAK-875) has dual potentiating mechanisms via Gαq-GPR40/FFAR1 signaling branches on glucose-dependent insulin secretion.

Fasiglifam (TAK-875) is a free fatty acid receptor 1 (FFAR1)/G-protein-coupled receptor 40 (GPR40) agonist that improves glycemic control in type 2 diabetes with minimum risk of hypoglycemia. Fasiglifam potentiates glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells glucose dependently, although the precise mechanism underlying the glucose dependency still remains unknown. Here, we investigated key cross-talk between the GSIS pathway and FFAR1 signaling, and Ca(2+) dynamics using mouse insulinoma MIN6 cells. We demonstrated that the glucose-dependent insulinotropic effect of fasiglifam required membrane depolarization and that fasiglifam induced a glucose-dependent increase in intracellular Ca(2+) level and amplification of Ca(2+) oscillations. This differed from the sulfonylurea glimepiride that induced changes in Ca(2+) dynamics glucose independently. Stimulation with cell-permeable analogs of IP3 or diacylglycerol (DAG), downstream second messengers of Gαq-FFAR1, augmented GSIS similar to fasiglifam, indicating their individual roles in the potentiation of GSIS pathway. Intriguingly, the IP3 analog triggered similar Ca(2+) dynamics to fasiglifam, whereas the DAG analog had no effect. Despite the lack of an effect on Ca(2+) dynamics, the DAG analog elicited synergistic effects on insulin secretion with Ca(2+) influx evoked by an L-type voltage-dependent calcium channel opener that mimics glucose-dependent Ca(2+) dynamics. These results indicate that the Gαq signaling activated by fasiglifam enhances GSIS pathway via dual potentiating mechanisms in which IP3 amplifies glucose-induced Ca(2+) oscillations and DAG/protein kinase C (PKC) augments downstream secretory mechanisms independent of Ca(2+) oscillations.

Discovery of a novel series of indoline carbamate and indolinylpyrimidine derivatives as potent GPR119 agonists.

GPR119 has emerged as an attractive target for anti-diabetic agents. We identified a structurally novel GPR119 agonist 22c that carries a 5-(methylsulfonyl)indoline motif as an early lead compound. To generate more potent compounds of this series, structural modifications were performed mainly to the central alkylene spacer. Installation of a carbonyl group and a methyl group on this spacer significantly enhanced agonistic activity, resulting in the identification of 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]propyl 7-fluoro-5-(methylsulfonyl)-2,3-dihydro-1H-indole-1-carboxylate (20). To further expand the chemical series of indoline-based GPR119 agonists, several heterocyclic core systems were introduced as surrogates of the carbamate spacer that mimic the presumed active conformation. This approach successfully produced an indolinylpyrimidine derivative 37, 5-(methylsulfonyl)-1-[6-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]-2,3-dihydro-1H-indole, which has potent GPR119 agonist activity. In rat oral glucose tolerance tests, these two indoline-based compounds effectively lowered plasma glucose excursion and glucose-dependent insulin secretion after oral administration.

Optimization of (2,3-dihydro-1-benzofuran-3-yl)acetic acids: discovery of a non-free fatty acid-like, highly bioavailable G protein-coupled receptor 40/free fatty acid receptor 1 agonist as a glucose-dependent insulinotropic agent.

G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic ß-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 µM (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to ß-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.

Discovery of phenylpropanoic acid derivatives containing polar functionalities as potent and orally bioavailable G protein-coupled receptor 40 agonists for the treatment of type 2 diabetes.

As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4'-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.

Identification of fused-ring alkanoic acids with improved pharmacokinetic profiles that act as G protein-coupled receptor 40/free fatty acid receptor 1 agonists.

The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to ß-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.

Discovery of a novel acyl-CoA: cholesterol acyltransferase inhibitor: the synthesis, biological evaluation, and reduced adrenal toxicity of (4-phenylcoumarin)acetanilide derivatives with a carboxylic acid moiety.

As a part of our research for novel potent and orally available acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors that can be used as anti-atherosclerotic agents, we recently reported the discovery of the (4-phenylcoumarine)acetanilide derivative 1. However, compound 1 showed adrenal toxicity in animal models. In order to search for safer ACAT inhibitors that do not have adrenal toxicity, we examined the inhibitory activity of ACAT in human macrophage and adrenal cells. The introduction of a carboxylic acid moiety on the pendant phenyl ring and the adjustment of the lipophilicity led to the discovery of (2E)-3-[7-chloro-3-[2-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]acrylic acid (21e), which showed potent ACAT inhibitory activity in macrophages and a selectivity of around 30-fold over adrenal cells. In addition, compound 21e showed high adrenal safety in guinea pigs.

TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats.

G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic ß cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. The insulinotropic action of TAK-875 (10 µM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired ß cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of ß cell toxicity.

Design, synthesis, and biological activity of potent and orally available G protein-coupled receptor 40 agonists.

G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic ß-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC(50) = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC(50) = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.

Rabbit plaque models closely resembling lesions in human coronary artery disease.

BACKGROUND: A suitable animal model is required to investigate plaque biology. Here, we examined 6 rabbit models of plaque generated by balloon injury and sequential combinations of normal and high-cholesterol diets. METHODS AND RESULTS: Fifty-eight male Japanese White rabbits were used. Lipid-rich macrophages accumulated in the center of the intima, and smooth muscle cells were located on the luminal side of the intima (similar to stable plaques in human coronary arteries) of a model in which balloon injury was followed by a normal diet for 4 weeks and then by a high-cholesterol diet for 4 weeks. Extending the high-cholesterol diet for a further 4 weeks increased accumulation of lipid-rich macrophages, diminished the amounts of elastic fibers and smooth muscle cells in the intima and caused the expression of matrix metalloproteinase-9 and tissue factor. All of these features are characteristic of unstable plaques. Moreover, quantitative analysis revealed that matrix metalloproteinase-9 expression and elastic-fiber content inversely correlated with statistical significance (R(2) = 0.52, p = 0.0003). CONCLUSION: A high-cholesterol diet for 0 to 8 weeks after a normal diet for the first 4 weeks following balloon injury induced various arterial lesions resembling the diffuse intimal thickening, as well as stable and unstable plaques that accumulate in human coronary arteries. The present models might be useful for plaque studies.

Switching to aggressive statin improves vascular endothelial function in patients with stable coronary artery disease.

AIM: The clinical relevance of the suggested pleiotropic effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) is controversial. Aggressive statins effectively reduce lipid levels, but whether their other effects are more powerful than those of regular statins is unknown. METHODS: We enrolled 32 patients (mean age, 65 y; male, 23) who had undergone coronary revascularization over 6 months previously and whose serum LDL cholesterol levels persisted at >100 mg/dL, regardless of pravastatin (10 mg/day). Before and 1 and 6 months after switching to atorvastatin (10 mg/day), we evaluated lipid profiles, including RLP-C (remnant-like particle cholesterol), high sensitive CRP (hsCRP), soluble CD40 ligand (sCD40L), TBARS (thiobarbituric acid reactive substances), and endothelial function determined from flow-mediated dilation (FMD) of the brachial artery. RESULTS: One month on atorvastatin lowered LDL cholesterol by 24% (131 to 100 mg/dL, p<0.001). In addition, RLP-C, sCD40L and hsCRP significantly decreased, whereas FMD did not change. After 6 months of this therapy, FMD significantly improved compared to baseline values (5.1 vs 3.6%, p=0.04). Changes in FMD and in total and RLP cholesterol significantly correlated. Moreover, FMD was remarkably improved in patients who achieved target LDL levels (<100 mg/dL). CONCLUSIONS: Switching from a regular to an aggressive statin can improve endothelial function at 6 months in patients with previous coronary artery disease. This effect is suggested to be mainly due to the lipid-lowering effect. Achievement and maintenance of the target LDL level by switching statins is beneficial in the clinical setting.

Possible de novo CTG repeat expansion in the DMPK gene of a patient with cardiomyopathy.

CTG triplet repeats of "normal" length in the myotonic dystrophy protein kinase (DMPK) gene have been previously believed to be stable and new pathological expansion was not believed to occur. Here we report possible de novo CTG repeat expansion in the DMPK gene in a patient with cardiomyopathy, who was not diagnosed as having myotonic dystrophy type 1 (DM1) by conventional genetic tests.

Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist.

GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic ß-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclization of the phenylpropanoic acid moiety of lead compound 1 produced fused phenylalkanoic acids with favorable in vitro agonist activities and pharmacokinetic profiles. Further optimization led to the discovery of dihydrobenzofuran derivative 9a ([(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate, TAK-875) as a potent, selective, and orally bioavailable GPR40 agonist, with a pharmacokinetic profile enabling long-acting drug efficacy. Compound 9a showed potent plasma glucose-lowering action and insulinotropic action during an oral glucose tolerance test in female Wistar fatty rats with impaired glucose tolerance. Compound 9a is currently in clinical trials for the treatment of type 2 diabetes mellitus.

Adrenal androgen dehydroepiandrosterone sulfate inhibits vascular remodeling following arterial injury.

Recent epidemiologic studies have suggested that serum dehydroepiandrosterone sulfate (DHEAS) levels have a significant inverse correlation with the incidence of cardiovascular diseases. However, direct evidence for the association with DHEAS and vascular disorders has not yet been explored. DHEAS significantly reduced neointima formation 28 days after surgery without altering other serum metabolite levels in a rabbit carotid balloon injury model. Immunohistochemical analyses revealed the reduction of proliferating cell nuclear antigen (PCNA) index and increase of TdT-mediated dUTP-biotin Nick End Labeling (TUNEL) index, expressing differentiated vascular smooth muscle cell (VSMC) markers in the media 7 days after surgery. In vitro, DHEAS exhibited inhibitory effects on VSMC proliferation and migration activities, inducing G1 cell cycle arrest with upregulation of one of the cyclin dependent kinase (CDK) inhibitors p16(INK4a) and apoptosis with activating peroxisome proliferator-activated receptor (PPAR)-alpha in VSMCs. DHEAS inhibits vascular remodeling reducing neointima formation after vascular injury via its effects on VSMC phenotypic modulation, functions and apoptosis upregulating p16(INK4a)/activating PPARalpha. DHEAS may play a pathophysiological role for vascular remodeling in cardiovascular disease.

Asymptomatic acute ischemic stroke after primary percutaneous coronary intervention in patients with acute coronary syndrome might be caused mainly by manipulating catheters or devices in the ascending aorta, regardless of the approach to the coronary artery.

BACKGROUND: Asymptomatic acute ischemic stroke (aAIS) following primary percutaneous coronary intervention (p-PCI) in patients with acute coronary syndrome (ACS) has not been studied in detail. METHODS AND RESULTS: Of 75 patients who underwent p-PCI, 26 (34.7%) developed aAIS as determined by diffusion-weighted magnetic resonance imaging (MRI). Including the approach to the coronary artery (via lower limb or right upper limb), 23 factors were compared between patients with (n=26) and without (n=49) aAIS. Age, hypertension, smoking, plasma glucose levels, Killip grade, right coronary artery (RCA) as culprit vessel, percutaneous coronary intervention (PCI) time, and the frequency of device insertion into the coronary artery differed in a statistically significant manner. However, multivariate analysis showed that the RCA (odds ratio 3.477) and the frequency of device insertion (1.375) were independent factors linked to the incidence of aAIS. Moreover, anterior or posterior location and left or right cerebral circulation of aAIS were equivalent in both approaches. CONCLUSIONS: Cranial MRI images following emergency PCI revealed that 34.7% of the patients with ACS had aAIS that might be caused by manipulating the catheter or devices in the ascending aorta, micro-air bubble embolism during injection, or micro-thrombus embolism derived from the ACS lesions during the PCI procedure.

Angiotensin receptor-1 blocker inhibits atherosclerotic changes and endothelial disruption of the aortic valve in hypercholesterolemic rabbits.

OBJECTIVES: We sought to examine the effect of angiotensin receptor blocker (ARB) on the formation of lesions in the aortic valves of hypercholesterolemic rabbits. BACKGROUND: Recently, atherosclerosis has been recognized as a mechanism that is responsible for calcific aortic stenosis. The effect of ARBs might help to prevent aortic stenosis because they have multiple antiatherosclerotic effects. METHODS: Male Japanese white rabbits (n = 36) were separated as follows: control with chow diet (C) and vehicle (V) groups, both of which were fed a 1% cholesterol diet for 8 weeks, and an ARB group (A), which was fed a 1% cholesterol diet for 8 weeks with ARB (olmesartan, 1 mg/kg/day) for the last 4 weeks. RESULTS: This dose of olmesartan did not affect either blood pressure or cholesterol levels. Dietary cholesterol induced fatty deposition with macrophage accumulation and osteopontin coexpression in valve leaflets, whereas ARB decreased macrophage accumulation (% area: V, 9.3 +/- 0.34; A, 1.4 +/- 0.30; p = 0.003) and osteopontin expression (p = 0.017). Angiotensin-converting enzyme was also up-regulated in V and decreased by olmesartan (p = 0.015). Immunohistochemistry with anti-CD31 antibody revealed that dietary cholesterol disrupted and olmesartan preserved endothelial integrity on the lesion-prone aortic side of the valve (% CD31-positive circumference: V, 30 +/- 3.7; A, 62 +/- 4.8; p = 0.003). Numbers of alpha-smooth muscle actin-positive myofibroblasts were increased in V and decreased by olmesartan (p = 0.003). Real-time polymerase chain reaction revealed that increased amounts of messenger ribonucleic acid for osteoblast-specific transcription factor core binding factor alpha-1 in V were diminished by olmesartan. CONCLUSIONS: Atherosclerotic changes in the aortic valves of rabbits fed with cholesterol were inhibited by ARB, whereas endo-thelial integrity was preserved and transdifferentiation into myofibroblasts and/or osteoblasts in valve leaflets was inhibited.

Young adult patients with short dissection length and thrombosed false lumen without ulcer-like projections are liable to have false-negative results of D-dimer testing for acute aortic dissection based on a study of 113 cases.

BACKGROUND: Previous reports indicate that D-dimer testing (DT) for acute aortic dissection (AAD) has a sensitivity of 100%, but each study comprised less than 30 patients. The aim of this study was to evaluate the positive rate and factors related to the results of DT for AAD in a larger population. METHODS AND RESULTS: DT (cutoff; upper normal limit) was performed for 113 consecutive AAD patients within 24 h of symptom onset. In total, 104 (92%) patients exhibited positive DT. The positive rate of DT showed a low tendency in patients aged less than 70 years and for a time interval from symptom onset to admission within 120 min, and there were significant differences between those with and without a thrombosed false lumen (TFL) (86.4% (n=59) vs 98.1% (n=54), p=0.033), complete TFL (excluding patients with ulcer-like projection (ULP) from those with a TFL) (81.1% (n=37) vs 97.4% (n=76), p=0.005) and length score (1 (n=28); 78.6%, 2 (n=40); 95.0%, 3 (n=45); 97.8%, p=0.005). Multivariate analysis demonstrated age (odds ratio =1.164, p=0.013), complete TFL (0.048, 0.030) and length score (6.271, 0.033) as independent factors. CONCLUSIONS: Physicians should be aware that younger patients with short dissection length and a TFL without ULP are liable to have false-negative DT results.

Vascular Behçet's disease with coronary artery aneurysm.

A 33-year-old man with a 4-year history of Behçet's disease was hospitalized with acute myocardial infarction. Percutaneous coronary intervention (PCI) treated 99% stenosis of the right coronary artery but follow-up coronary arteriography clearly revealed a coronary artery aneurysm (CAA) at the lesion proximal to the PCI site and intravascular ultrasound confirmed that it was a true aneurysm. We speculated that Behçet's disease might be involved in coronary lesion, especially in CAA formation. We decided to increase the dose of prednisolone and to add warfarin. The size of the CAA was not altered after 6 months.