Tomomi Ota

Protective effects of SEA0400, a novel and selective inhibitor of the Na+/Ca2+ exchanger, on myocardial ischemia-reperfusion injuries

The Na(+)/Ca(2+) exchanger (NCX) is involved in myocardial ischemia-reperfusion injuries. We examined the effects of 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a potent and selective inhibitor of NCX, on myocardial ischemia-reperfusion injury models. In canine cardiac sarcolemmal vesicles and rat cardiomyocytes, SEA0400 potently inhibited the Na(+)-dependent 45Ca(2+) uptake with an IC(50) value of 90 and 92 nM, compared with 2-[2-[4-(4-nitrobenzyloxy)phenyl]isothiourea (KB-R7943, 7.0 and 9.5 microM), respectively. In rat cardiomyocytes, SEA0400 (1 and 3 microM) attenuated the Ca(2+) paradox-induced cell death. In isolated rat Langendorff hearts, SEA0400 (0.3 and 1 microM) improved the cardiac dysfunction induced by low-pressure perfusion followed by normal perfusion. In anesthetized rats, SEA0400 (0.3 and 1 mg/kg, i.v.) reduced the incidence of ventricular fibrillation and mortality induced by occlusion of the left anterior descending coronary artery followed by reperfusion. These results suggest that SEA0400 is a most potent NCX inhibitor in the heart and that it has protective effects against myocardial ischemia-reperfusion injuries.

Development of a Method for Evaluating Drug-Likeness and Ease of Synthesis Using a Data Set in Which Compounds Are Assigned Scores Based on Chemists' Intuition

The concept of drug-likeness, an important characteristic for any compound in a screening library, is nevertheless difficult to pin down. Based on our belief that this concept is implicit within the collective experience of working chemists, we devised a data set to capture an intuitive human understanding of both this characteristic and ease of synthesis, a second key characteristic. Five chemists assigned a pair of scores to each of 3980 diverse compounds, with the component scores of each pair corresponding to drug-likeness and ease of synthesis, respectively. Using this data set, we devised binary classifiers with an artificial neural network and a support vector machine. These models were found to efficiently eliminate compounds that are not drug-like and/or hard-to-synthesize derivatives, demonstrating the suitability of these models for use as compound acquisition filters.

Chemoenzymatic synthesis of optically active 1,4-dihydropyridine derivatives via enantioselective hydrolysis and transesterification

Abstract (4 R )-(−)-2-(Nicotinoylamino)ethyl 3-nitrooxypropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate ( 1 ), a new calcium antagonist, was synthesized via both enantioselective hydrolysis and transesterification of prochiral bis[2-(nicotinoylamino)ethyl]ester · 2HCl ( 5 ) by using enzymes. Hydrolysis of 5 by proteases originated from Aspergillus melleus and Bacillus licheniformis etc. in aqueous media afforded (4 R )-(−)-3-[2-(nicotinoylamino)-ethoxycarbonyl]-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid ( 6 ) in more than 99% e.e., which was converted to 1 by esterification with 3-nitrooxypropyl bromide. Enzymatic transesterification of 5 with 3-nitrooxypropanol gave 1 in more than 99.5% e.e. directly.

Selective preparation and cyclization of 2-(2-hydroxyphenyl)-2-(isopropylthio)ethanols. New synthesis of 1-benzofurans

Reaction of phenols with 2-(isopropylthio)ethyl acetate activated by sulphuryl chloride afforded 2-[2-acetoxy-1-(isopropylthio)ethyl]phenols regioselectively, via[2,3]sigmatropic rearrangement of phenoxysulphonium ylides. The ortho-alkylated phenols thus obtained have been cyclized with conc. hydrochloric acid in 2-methoxyethanol to 1-benzofurans. 2-Methyl- and 2-phenyl-1-benzofurans have been prepared similarly.

Selective ortho-alkylation of phenols with sulphoxides via[2,3]sigmatropic rearrangement: synthesis of coumarins

ortho-Alkylphenols have been prepared from phenol and dialkyl sulphoxides via[2,3]sigmatropic rearrangement, using thionyl chloride or phenyl chlorosulphinate as an activator of sulphoxides. In the same manner, ortho-phenylthiomethylphenol has been prepared in good yield. When ethyl phenyl sulphoxide, diallyl sulphoxide, and methyl methylsulphinylacetate were used as sulphoxides, none of the expected products were obtained. Salicylaldehyde has been prepared in moderate yield, when methyl methylthiomethyl sulphoxide was used as a sulphoxide. 3-(2-Hydroxyphenyl)propionic acid derivatives, which were obtained from substituted phenols and dimethyl 3,3′-sulphinyldipropionate, have been cyclized to give the corresponding coumarins in good yields.

Effects of CD-832, a new calcium antagonist, on intracranial pressure in anesthetized dogs.

Effects of a new calcium antagonist, CD-832, on intracranial pressure (ICP), vertebral blood flow (VBF) and common carotid blood flow (CCBF) were investigated in dogs and the results were compared with findings for nifedipine and diltiaem. Dogs were anesthetized with sodium pentobarbital and a 20-gauge needle was inserted into the cisterna magna for ICP determination. Mean arterial blood pressure (MBP), heart rate (HR), CP, VBF and CCBF were measured before and during the continuous intravenous infusion of CD-832 (0.3, 1 and 3 microg/kg/min), nifedipine (0.1, 0.3 and 1 microg/kg/min) or diltiazem (1, 3 and 10 microg/kg/min). Although the three drugs caused a comparable hypotension, differences were evident in effects of these agents on ICP, VBF and CCBF. Nifedipine and diltiazem but not CD-832 significantly increased ICP, VBF and CCBF. These results suggest that CD-832 is a unique calcium antagonist which does not increase ICP during hypotension. Because the most evident side effects of calcium antagonists are caused by vasodilation and include headache and flushing, CD-832 may possibly be useful to treat subjects with hypertension or angina pectoris.