DSR-71167, a novel mineralocorticoid receptor antagonist with carbonic anhydrase inhibitory activity, separates urinary sodium excretion and serum potassium elevation in rats.

Mineralocorticoid receptor (MR) antagonists, such as spironolactone (SPI) and eplerenone (EPL), are useful for treating hypertension and heart failure. However, these two agents have the serious side effect of hyperkalemia. We hypothesized that adding the ability to inhibit carbonic anhydrase (CA) would reduce the risk of hyperkalemia associated with MR antagonists. We investigated the profiles of DSR-71167 [2-([(2,2-difluoroethyl)amino]methyl)-2'-fluoro-N-(3-methoxy-4-sulfamoylphenyl)biphenyl-4-carboxamide hydrochloride; an MR antagonist with weak CA inhibitory activity] with regard to antimineralocorticoid actions by examining relationships between the urinary excretion of sodium (index of antimineralocorticoid action) in deoxycorticosterone acetate-treated rats and elevation of serum levels of potassium in potassium-loaded rats compared with a DSR-71167 derivative without CA inhibition (2-(hydroxymethyl)-N-[4-(methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide), SPI, and EPL. DSR-71167 dose-dependently increased urinary excretion of sodium in deoxycorticosterone acetate-treated rats without elevating serum levels of potassium in potassium-loaded rats. 2-(Hydroxymethyl)-N-[4-(methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide, SPI, and EPL elevated serum levels of potassium significantly in potassium-loaded rats at doses that increased MR inhibitory activity. We confirmed that DSR-71167 significantly increases urinary bicarbonate and decreases blood bicarbonate, as pharmacodynamic markers of CA inhibition, in intact rats. Chronic DSR-71167 administration showed antihypertensive effects in high salt-loaded Dahl hypertensive rats. These results demonstrate that DSR-71167 is a novel type of MR antagonist, with CA inhibitory activity, which is expected to become a safer MR antagonist with a low potential risk for hyperkalemia.

Effect of ecabet sodium treatment on urea breath test and stool antigen tests in volunteers with Helicobacter pylori infection.

BACKGROUND AND AIM: Ecabet sodium is reported to have a bactericidal effect on Helicobacter pylori and inhibit urease activity in vitro. METHODS: Seven male volunteers (mean age, 51.3 years; range, 45-55 years) with H. pylori infection were medicated with 1 g ecabet sodium t.i.d. for 4 weeks. The urea breath test (UBT) was performed 10 times per person: before medication, seven times in 2 weeks, and once in the third and fourth weeks. Stool antigen tests (HpSA PLUS and Testmate pylori antigen) were performed five times per person: before medication and weekly during medication. RESULTS: The premedication UBT value ranged from 4.9 ‰ to 77.4 ‰ and from 2.9 ‰ to 44 ‰ at the end of the treatment period. Not one of the subjects had a negative UBT result during medication. The optical densities of the HpSA and Testmate pylori antigen tests ranged from 0.4 to > 3.0 premedication and from 0.0 to > 3.0 at the end of treatment. HpSA and Testmate pylori antigen were negative in two cases. CONCLUSIONS: In this study, ecabet sodium did not effect the results of UBT in volunteers with H. pylori infection. Ecabet sodium may influence stool antigens because in two of seven cases the H. pylori stool antigen tests returned negative results.

Second generation catalytic asymmetric synthesis of Tamiflu: allylic substitution route.

Catalytic asymmetric synthesis of Tamiflu, an important antiinfluenza drug, was achieved. After the catalytic enantioselective desymmetrization of meso-aziridine 3 with TMSN3, using a Y catalyst (1 mol %) derived from ligand 2, an allylic oxygen function and C1 unit on the C=C double bond were introduced through cyanophosphorylation of enone and allylic substitution with an oxygen nucleophile. This second generation route of Tamiflu is more practical than our previously reported route. [reaction: see text].

Safety and efficacy of carbon dioxide and intravascular ultrasound-guided stenting for renal artery stenosis in patients with chronic renal insufficiency.

We evaluated the feasibility, safety, and mid-term outcomes of renal artery stenting using carbon dioxide (CO2) digital subtraction angiography and intravascular ultrasound (IVUS) for patients with renal insufficiency and significant atherosclerotic renal artery stenosis (RAS). Eighteen consecutive patients with chronic renal insufficiency underwent renal artery stenting under the guidance of CO2 angiography and IVUS without contrast media. Renal function and blood pressure were assessed pre- and postintervention. A total of 27 de novo RAS in 18 patients (15 males; mean age: 72 ± 9 years) with renal insufficiency were treated by renal artery stenting with the combined use of the CO2 angiography and IVUS without any procedural complications. Although the mean serum creatinine concentration preprocedure and 6 months after treatment did not change (2.7 ± 1.0-2.4 ± 1.1 mg/dL), blood pressure significantly decreased 6 months after stenting (158 ± 10-147 ± 11 mm Hg, P < .01).

Total synthesis of lactacystin and salinosporamide A.

Lactacystin and salinosporamide A are fascinating molecules with regard to both their chemical structures and biological activities. These naturally occurring compounds are potent and selective proteasome inhibitors. The molecular structures are characterized by their densely functionalized gamma-lactam cores. The structure and biological properties of these two compounds are attracting the attention of many chemists as challenging synthetic targets. We discuss their synthetic strategies in this review.

De novo synthesis of Tamiflu via a catalytic asymmetric ring-opening of meso-aziridines with TMSN3.

An asymmetric ring-opening reaction of meso-aziridines with TMSN3 was developed using a catalyst prepared from Y(OiPr)3 and chiral ligand 2 in a 1:2 ratio. Excellent enantioselectivity was realized from a wide range of substrates with a practical catalyst loading. The products were efficiently converted to enantiomerically enriched 1,2-diamines, which are versatile chiral building blocks for pharmaceuticals and chiral ligands. This reaction was applied to a catalytic asymmetric synthesis of Tamiflu, a very important anti-influenza drug containing a chiral 1,2-diamino functionality.

Catalytic asymmetric total synthesis of (+)-lactacystin.

Total synthesis of (+)-lactacystin, a potent and selective proteasome inhibitor, was accomplished using a catalytic enantioselective Strecker reaction of a ketoimine as the initial key step. An enone-derived N-phosphinoyl ketoimine 7 was selected as a stable masked alpha-hydroxy ketoimine analogue. Excellent enantioselectivity (98% ee) and practical catalyst activity were produced under the optimized catalyst preparation method using 2.5 mol % Gd{N(SiMe3)2}3 as a metal source and 3.8 mol % D-glucose-derived ligand 8. This reaction was conducted on a 5 g scale. The chiral tetrasubstituted C-5 carbon efficiently controlled the stereochemistry of the other three chiral centers of lactacystin. Chelation-controlled Meerwein-type reduction of ketone 5 using i-PrMgBr (originally reported by Kang in a related substrate) selectively produced the desired secondary alcohol at the C-9 position. The C-6 hydroxy and C-7 methyl groups were introduced via a silyl conjugate addition followed by the Tamao oxidation and Donohoe methylation, respectively, in a highly stereoselective manner. A practical amount of enantiomerically pure clasto-lactacystin beta-lactone (2), the biologically active form of (+)-lactacystin, can be synthesized using this route. clasto-Lactacystin beta-lactone (2) was converted to (+)-lactacystin following the reported procedure.

Asymmetric total synthesis of fredericamycin A: an intramolecular cycloaddition pathway.

The asymmetric total synthesis of the potent antitumor antibiotic fredericamycin A ((S)-1) was achieved by the intramolecular [4+2] cycloaddition of the silylene-protected styrene derivative (S)-7 followed by the aromatic Pummerer-type reaction of the sulfoxide (S)-5. Although we had already succeeded in the total synthesis of racemic 1 by the same approach, synthesis of its asymmetric version was more complicated than we had expected due to the difficulties involved in constructing the quaternary carbon center and the tendency of this center to undergo facile racemization. Racemization of this center during the installation of the acetylene moiety on the dione (R)-8 was the most serious aspect. Systematic studies of its DE-ring analogue (R)-25 revealed that racemization of the quaternary carbon center proceeded by a retro-aldol-aldol reaction of the initial adduct, (1R)-39 a-Li, and that the degree of racemization was dependent on the reaction temperature. The racemization process could be completely depressed by keeping the reaction temperature at -78 degrees C. The construction of the stereogenic quaternary carbon center was achieved by the lipase-catalyzed desymmetrization of the prochiral 1,3-diol 9 a bearing the DEF-ring moiety. These studies enabled us to attain the asymmetric total synthesis of (S)-1 while completely retaining the chiral integrity created by the enzymatic reactions.