Survival study by organ disorders in 306 Japanese patients with systemic lupus erythematosus: results from a single center.

Survival rate and causes of death according to the period of diagnosis and four accompanying organ disorders were analyzed in 306 Japanese patients with systemic lupus erythematosus. The survival rate was gradually improved, and the survival rate during 5- and 10-year periods of the patients diagnosed in 1990-2004 was 94 and 92%, 20-year period of those in 1980-1989 was 77%, 30-year period of those in 1975-1979 was 71%, respectively. Survival rate of those with serositis, pulmonary hypertension, and positive family history tended to be reduced, while that of the cases with neuropsychiatric disorder and renal disorder was significantly reduced. Overlapping of these organ disorders was an important factor for a poor prognosis. Bronchopneumonia and cerebrovascular accidents were frequent causes of death, and treatment for anti-phospholipid antibody syndrome and life-style diseases such as hypertension and arteriosclerosis was thought to be important for a good outcome.

Potent and selective ET-A antagonists. 1. Syntheses and structure-activity relationships of N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives.

Modifications to the ET(A/B) mixed type compounds 1 (Ro. 46-2005) and 2 (bosentan) were performed. Introduction of a pyrimidine group into 1 resulted in a dramatic increase in affinity for the ET(A) receptor, and the subsequent optimization of substituents on the pyrimidine ring led us to the discovery of N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)-4-pyrimidinyl)-4-tert-butylbenzenesulfonamide (7k), which showed an extremely high affinity for the human cloned ET(A) receptor (K(i) = 0.0042 +/- 0.0038 nM) and an ET(A/B) receptor selectivity up to 29 000 (K(i) = 130 +/- 50 nM for the human cloned ET(B) receptor). The compound was designed on the hypothesis that the hydrogen atom of the hydroxyl group in 1 and 2 played a role not as a proton donor but as an acceptor in the possible hydrogen bonding with Tyr129. Since the incorporation of a pyrimidinyl group into the hydroxyethoxy side chain of the nonselective antagonist (1) dramatically enhanced both the ET(A) receptor affinity and selectivity, and since similar results were obtained from the benzene analogues, we put forward the hypothesis that a "pyrimidine binding pocket" might exist in the ET(A) receptor.

Potent and selective ET-A antagonists. 2. Discovery and evaluation of potent and water soluble N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives.

In the preceding article,(1) we outlined the discovery and structure-activity relationship of a potent and selective ET(A) receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ET(A) receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ET(A) receptor (K(i) for ET(A) receptor: 0.015 +/- 0.004 nM; for ET(B) receptor: 41 +/- 21 nM).

An efficient synthesis of the anti-asthmatic agent T-440: a selective N-alkylation of 2-pyridone.

6,7-Diethoxy-1-[1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridin- 4-yl]naphthalene-2,3-dimethanol [T-440, (1)] is a potential anti-asthmatic agent based on selective phosphodiesterase 4 inhibition. It was necessary for the further evaluation of 1 to develop an efficient synthetic route for 1, especially the construction of the 1-(2-methoxyethyl)-2-pyridone moiety. We examined an N-selective alkylation of pyridone derivative (2) in basic media. 2-Methoxyethylation of 2 with 2-methoxyethyl iodide utilizing LiH as the base gave predominantly an N-alkyl pyridone derivative (3a) in 82% yield (N/O-alkylation=92/8), which is compatible with an ab initio calculation of transition-state structures for the methylation of 2-pyridone. Single crystallization of a crude mixture of 3a and 4a furnished pure 3a, which is a key synthetic intermediate of 1.

Biodistribution of 3,4-dihydro-5-[11C]methoxy-1(2H)-isoquinolinone, a potential PET tracer for poly(ADP-ribose) synthetase.

Poly(adenosine diphosphate-ribose) synthetase (PARS) is a nuclear enzyme that is activated by deoxyribonucleic acid (DNA) strand breaks and participates in DNA repair. Excessive PARS activation, however, leads to cell death due to depletion of adenosine triphosphate (ATP). To evaluate whether it is possible to detect excessive activation of PARS with positron emission tomography (PET), we examined the pharmacokinetics of 3,4-dihydro-5-[(11)C]methoxy-1(2H)-isoquinolinone ([(11)C]MIQO), a potent poly(ADP-ribose) synthetase inhibitor, in the brain of rats and monkeys. Although the uptake of [(11)C]MIQO in the brain of normal rats was low, [(11)C]MIQO was rapidly incorporated into and then quickly washed out from the brain. The uptake of the radiotracer in the brain of normal monkeys was also low; however, [(11)C]MIQO gave a distribution image that differed from that of cerebral blood flow obtained by [(15)O]water-PET. No localization of [(11)C]MIQO in the brain of normal monkeys was observed. Low accumulation of some radioactivity was also observed in muscles surrounding the brain of monkeys, but did not seem to interfere with measurement of [(11)C]MIQO uptake in the brain with PET. Thus, detection of [(11)C]MIQO uptake with PET may be useful for detecting PARS activity in ischemic injury.