G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic β 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)propoxybiphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-ylacetic 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 β 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 β cell toxicity.
GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-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)propoxybiphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-ylacetic 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.
Angiotensin Receptor-1 Blocker Inhibits Atherosclerotic Changes and Endothelial Disruption of the Aortic Valve in Hypercholesterolemic Rabbits Kumiko Arishiro, Masaaki Hoshiga, Nobuyuki Negoro, Denan ...Jin, Shinji Takai, Mizuo Miyazaki, Tadashi Ishihara, Toshiaki Hanafusa Angiotensin receptor blockers (ARBs) might help to prevent aortic stenosis because they have multiple antiatherosclerotic effects. We investigated the effects of ARB (olmesartan) on lesion formation of aortic valves in hypercholesterolemic rabbits. The use of ARB inhibited cholesterol-induced lesion formation of aortic valve as well as macrophage accumulation, osteopontin coexpression, up-regulation of angiotensin-converting enzyme, disruption of endothelial integrity of valve surface, differentiation into myofibroblasts, and induction of osteoblast-specific transcription factor, without altering cholesterol level or blood pressure. These findings may have important prognostic implications for clinical use of blockers of the renin-angiotensin system in patients with aortic valve stenosis.
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)pyrazolo1,5-apyrimidine-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.
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 β-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 β-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.
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 β-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.
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. (Circ J 2006; 70: 1598 - 1601)
Background It is important to rapidly distinguish patients with acute aortic dissection of the ascending aorta (AADa) from those with acute myocardial infarction (AMI), because minimizing the time to ...initiation of reperfusion therapy leads to maximum benefits for AMI and erroneous reperfusion therapy for AADa can produce harmful outcomes. The aim of this study was to find a simple test to distinguish such patients. Methods and Results Data were collected from 29 consecutive patients with AADa and 49 consecutive patients with AMI who were admitted within 4 h of the onset of symptoms. The D-dimer concentration and the ratio of the maximum upper mediastinal diameter to the maximum thoracic diameter on plain chest radiograph (M-ratio) in the emergency room were studied retrospectively. Setting the cutoff values of the D-dimer concentration and the M-ratio to 0.8 or 0.9 μg/ml and 0.309, respectively, gave a sensitivity of 93.1% and 93.1% for AADa, respectively, and a sensitivity of 91.8% and 85.7% for AMI, respectively. Conclusions The D-dimer value and the M-ratio, with appropriate cutoff values, have potential as tests that can be routinely used to exclude AADa patients from patients diagnosed with AMI prior to reperfusion therapy. (Circ J 2005; 69: 677 - 682)
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)phenylamino-2-oxoethyl-6-methyl-2-oxo-2H-chromen-4-ylphenylacrylic 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.
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.
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