Pyridylmethylthio derivatives as VEGF inhibitors. Part 1

Optimization from compound 4a, having intramolecular S-O nonbonded interaction, led to discover compounds 4m and 4n. They were highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, AMD).     

Synthetic studies on selective adenosine A2A receptor antagonists. Part II: Synthesis and structure–activity relationships of novel benzofuran derivatives

Based on the previously reported lead compound, a series of benzofuran derivatives were prepared to study their antagonistic activities to A_2A receptor. The replacement of the phenyl group at the 4-position with a heterocyclic ring improved the PK profile and aqueous solubility. From these studies, we discovered a potent new A_2A antagonist, 12a, which has both a good oral bioavailability and in vivo efficacy on motor disability in MPTP-treated common marmosets.     

A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome

AimsDisrupted-in schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and major depressive disorder (MDD). Patients with chronic fatigue syndrome (CFS) report having continuous severe fatigue and many overlapping symptoms with MDD; however, the mechanism and effective treatment of CFS are still unclear. We focused on the overlapping symptoms between CFS and MDD and performed an association study of the functional single-nucleotide polymorphism (SNP) in the DISC1 gene with CFS.Main methodsVenous blood was drawn from CFS patients and controls and genomic DNA was extracted from the whole blood according to standard procedures. Ser704Cys DISC1 SNP was genotyped using the TaqMan 5′-exonuclease allelic discrimination assay.Key findingsWe found that the Cys704 allele of Ser704Cys SNP was associated with an increased risk of CFS development compared with the Ser704 allele.SignificanceDISC1 Ser704Cys might be a functional variant that affects one of the mechanisms implicated in the biology of CFS. Some patients with CFS showed a phenotype similar to that of patients with MDD, but further studies are needed to clarify the biological mechanism, because this study is of a rather preliminary nature. Despite the variety of patients with CFS, DISC1 Ser704Cys has an association with CFS, which may also suggest that DISC1 plays a central role in the induction of various psychiatric diseases.     

Fat-free mass and excess post-exercise oxygen consumption in the 40 minutes after short-duration exhaustive exercise in young male Japanese athletes

The relationship between fat-free mass (FFM) and excess post-exercise oxygen consumption (EPOC) has not been well researched because of the relatively small number of subjects studied. This study investigated the effects of FFM on EPOC and EPOC/maximum oxygen consumption. 250 Japanese male athletes between 16 and 21 years old from Nagasaki prefecture had their EPOC measured up to 40 minutes after short-duration exhaustive exercise. The value was named as EPOC40 min. The proportions of EPOC up to 1, 3, 6, 10, and 25 minutes to EPOC40 min were calculated and named as P1, P3, P6, P10, and P25, respectively. Body size and composition, VO2max and resting metabolic rate (RMR) were also measured. Mean EPOC40 min was 9.04 L or 158 ml/kg FFM. EPOC40 min was related to FFM (r=0.55, p<0.001) and VO2max (r=0.37, p<0.001). The ratio of EPOC40 min to VO2max was related to FFM (r=0.28, p<0.001). P1, P3, P6, P10, and P25 were negatively related to EPOC40 min/FFM, EPOC40 min/VO2max, and FFM. Athletes who had larger FFM had larger EPOC40 40 min and EPOC40 40 min/VO2max, and smaller P1, P3, P10, and P25.     

Ca2+-dependent dual functions of peptide C. The peptide corresponding to the Glu724-Pro760 region (the so-called determinant of excitation-contraction coupling) of the dihydropyridine receptor alpha 1 subunit II-III loop.

Both in vivo and in vitro studies suggest that the Glu(724)-Pro(760) (peptide C) region of the dihydropyridine receptor alpha1 II-III loop is important for excitation-contraction coupling, although its actual function has not yet been elucidated. According to our recent studies, peptide C inhibits Ca(2+) release induced by T-tubule depolarization or peptide A. Here we report that peptide C has Ca(2+)-dependent dual functions on the skeletal muscle ryanodine receptor. Thus, at above-threshold [Ca(2+)]s (> or =0.1 microm) peptide C blocked peptide A-induced activation of the ryanodine receptor (ryanodine binding and Ca(2+) release); peptide C also blocked T-tubule depolarization-induced Ca(2+) release. However, at sub-threshold [Ca(2+)]s (<0.1 microm), peptide C enhanced ryanodine binding and induced Ca(2+) release. If peptide A was present, together with peptide C, both peptides produced additive activation effects. Neither peptide A nor peptide C produced any appreciable effect on the cardiac muscle ryanodine receptor at both high (1.0 microm) and low (0.01 microm) Ca(2+) concentrations. These results suggest the possibility that the in vivo counterpart of peptide C retains both activating and blocking functions of the skeletal muscle-type excitation-contraction coupling.     

Intersubunit disulfide bridge is not required for the protective role of SP-B against lung inflammation.

Surfactant protein B (SP-B) is known to promote surfactant phospholipid film formation and reduce surface tension. Native SP-B is a homodimer in which subunit association is stabilized via covalent linkage through cysteine 48. We hypothesized that loss of the intersubunit bridge would alter SP-B function and lead to increased inflammation in response to challenge by hyperoxia or endotoxin. Transgenic mice in which SP-B cysteine 48 was mutated to serine were generated and crossed into the SP-B(-/-) background. Wild-type mice and transgenic mice carrying a single copy (SP-Bmon(+)) or two copies (SP-Bmon(++)) of the transgene were exposed to 95% O2 for 3 days or intratracheally injected with 10 microg of endotoxin. Interleukin-1beta, major intrinsic protein 2, and interleukin-6 in lung homogenates after 3 days of hyperoxia were significantly higher (P < 0.001) in SP-Bmon(+) mice than SP-Bmon(++) or wild-type mice. At 16 h after endotoxin injection, cytokines in lung tissues were higher in SP-Bmon(+) mice compared with wild-type mice (P < 0.05). Consistent with prolonged recovery in SP-Bmon(+) mice, the percentage of apoptotic cells in alveolar lavage was significantly lower in SP-Bmon(+) mice than in SP-Bmon(++) and wild-type mice. Overall, increased inflammation in SP-Bmon(+) mice was corrected to a large extent by increased gene dosage, indicating that formation of the intersubunit disulfide bridge is not critical for SP-B function.