Low fragment polyatomic molecular ion source by using permanent magnets.

Electron-ionization-type polyatomic molecular ion source with low fragment was developed by using a pair of ring-shaped Sm-Co magnets. The magnets were placed forward and backward side of ionization part to confine electrons extracted from a thermionic cathode. Calculated electron trajectory of the developed ion source was 20 times longer than that of an ordinary outer filament configuration that has no magnetic confinement. Mass spectra of the molecular ions generated from n-tetradecane (C14H30) gas exhibited 4 times larger intensity than that of the ordinary configuration in a range of mass/charge from 93 to 210 u. This indicates that suppression of fragment ion was obtained by increase of low energy electrons resulted from the electron confinement.

Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile.

Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.

Identification of a novel and orally available benzimidazole derivative as an NPY Y5 receptor antagonist with in vivo efficacy.

Optimization of lead compound 2 is described, mainly focusing on modification at the C-2 position of the benzimidazole core. Replacement of the phenyl linker of 2 with saturated rings resulted in identification of compound 8b which combines high Y5 receptor binding affinity with a good ADME profile leading to in vivo efficacy.

Design, synthesis and identification of novel benzimidazole derivatives as highly potent NPY Y5 receptor antagonists with attractive in vitro ADME profiles.

Optimization of our HTS hit 1, mainly focused on modification at the C-2 position of the benzimidazole core, is described. Elimination of the flexible and metabolically labile -S-CH(2)- part and utilization of less lipophilic pyridone substructure led to identification of novel NPY Y5 receptor antagonists 6, which have low to sub-nanomolar Y5 receptor binding affinity with improved CYP450 inhibition profiles, good solubilities and high metabolic stabilities.

Repeated chromosome splitting targeted to delta sequences in Saccharomyces cerevisiae.

We have previously developed a chromosome-splitting technique based on homologous recombination in Saccharomyces cerevisiae. To facilitate chromosome splitting at multiple sites, we focused on the delta sequences that are distributed in more than 200 copies throughout the yeast genome. We constructed a new chromosome-splitting vector harboring the YFLWdelta4 sequence and the hisG-URA3-hisG cassette, and transformed yeast cells with this vector. The karyotype analysis of transformants showed that chromosomes XIV, III, and IV, or other chromosomes are split. After the excision of the URA3 gene, the transformant with split chromosome IV was subsequently transformed with the same vector. Karyotype analysis revealed that further splitting occurred at chromosome X, the split chromosome IV, or other chromosomes. These results indicate that delta sequences are efficient target sites for repeated chromosome splitting at multiple sites with a single vector.