TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis,physicochemical and pharmacological properties

Crystalline 1 (TAK-599) is a novel N-phosphono prodrug of anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporin 2a (T-91825) that has high affinity for penicillin-binding protein (PBP) 2' (IC(50); 0.90 microg/mL) and shows potent in vitro anti-MRSA activity (MIC against MRSA N133; 1.56 microg/mL), comparable to that of vancomycin (1.56 microg/mL). Although 2a had insufficient water solubility (2.3 mg/mL) for parenteral administration, 1 showed excellent water solubility (>100 mg/mL, pH 7) as well as good chemical stability in the solid state and solution. In pharmacokinetic studies, when 1 was administered intravenously to rats and monkeys, it was rapidly converted into 2a in the blood. These results show that 1 (TAK-599) is a highly promising parenteral cephalosporin targeted for MRSA infection.     

Electromagnetic wave emitting products and “Kikoh” potentiate human leukocyte functions

Tourmaline (electric stone, a type of granite stone), common granite stone, ceramic disks, hot spring water and human palmar energy (called “Kikoh” in Japan and China), all which emit electromagnetic radiation in the far infrared region (wavelength 4–14 µm). These materials were thus examined for effects on human leukocyte activity and on lipid peroxidation of unsaturated fatty acids. It was revealed that these materials significantly increased intracellular calcium ion concentration, phagocytosis, and generation of reactive oxygen species in neutrophils, and the blastogenetic response of lymphocytes to mitogens. Chemotactic activity by neutrophils was also enhanced by exposure to tourmaline and the palm of “Kikohshi” i.e., a person who heals professionally by the laying on of hands. Despite the increase in reactive oxygen species generated by neutrophils, lipid peroxidation from unsaturated fatty acid was markedly inhibited by these four materials. The results suggest that materials emitting electromagnetic radiation in the far infrared range, which are widely used in Japan for cosmetic, therapeutic, and preservative purposes, appear capable of potentiating leukocyte functions without promoting oxidative injury.     

CCR5 antagonists as anti-HIV-1 agents. Part 2: Synthesis and biological evaluation of N-[3-(4-benzylpiperidin-1-yl)propyl]-N,N'-diphenylureas

We have previously reported the novel lead compound 1a as a CCR5 antagonist for treatment of HIV-1 infection. SAR studies on incorporating various acyl groups as a replacement for the 5-oxopyrrolidine-3-carbonyl group of the lead structure resulted in the discovery of N-[3-(4-benzylpiperidin-1-yl)propyl]-N,N'-diphenylurea (4a) with significantly improved CCR5 binding affinity. Substitutions (4-Cl, 4e,f; 4-Me, 4i) on the N'-phenyl ring further increased the binding affinity. Introduction of polar substituents on the phenyl ring of the 4-benzylpiperidine moiety enhanced the inhibitory activity of the HIV-1 envelope-mediated membrane fusion (4v,w), suggesting that polar substituents at this position can interfere effectively with HIV-1 cell entry.     

Orally active CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological activities of 1-benzazepine derivatives containing a sulfoxide moiety

In order to develop orally active CCR5 antagonists, 1-propyl- or 1-isobutyl-1-benzazepine derivatives containing a sulfoxide moiety have been designed, synthesized, and evaluated for their biological activities. Sulfoxide compounds containing a 2-pyridyl group were first investigated, which led to discovering that the presence of a methylene group between the sulfoxide moiety and 2-pyridyl group was necessary for increased inhibitory activity in a binding assay. After further chemical modification, it was found that replacement of the pyridyl group with an imidazolyl or 1,2,4-triazolyl group enhanced activity in the binding assay and that S-sulfoxide compounds were more active than R-isomers. Particularly, compounds (S)-4r, (S)-4s, and (S)-4w exhibited highly potent CCR5 antagonistic activities (IC50=1.9, 1.7, 1.6 nM, respectively) and inhibitory effects (IC50=1.0, 2.8, 7.7 nM, respectively) in the HIV-1 envelope mediated membrane fusion assay, together with good pharmacokinetic properties in rats. In addition, we established the synthesis of (S)-4r and (S)-4w by asymmetric oxidation with titanium-(S)-(-)-1,1'-bi-2-naphthol complex.     

CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological evaluation of piperidine-4-carboxamide derivatives

Replacement of the 5-oxopyrrolidin-3-yl fragment in the previously reported lead structure with a 1-acetylpiperidin-4-yl group led to the discovery of a novel series of potent CCR5 antagonists. Introduction of small hydrophobic substituents on the central phenyl ring increased the binding affinity, providing low to sub-nanomolar CCR5 antagonists. The selected compound 11f showed excellent antiviral activity against CCR5-using HIV-1 replication in human peripheral blood mononuclear cells (EC50=0.59 nM) and an acceptable pharmacokinetic profile in dogs.     

Host suitability of various stored food products for the cigarette beetle, <Emphasis Type="Italic">Lasioderma serricorne</Emphasis> (Coleoptera: Anobiidae)

We investigated the attraction to, and ovipositional activity and egg-to-adult survival rate on, 11 stored products of Lasioderma serricorne (F.). These products included polished rice, unpolished rice, wheat flour, corn flour, cocoa powder, roasted coffee beans, green tea leaves, black tea leaves, soybean flour, flue-cured tobacco leaves, and dried small sardines. Tobacco, cocoa, soybean flour, black tea, and wheat flour significantly attracted the beetles. Corn flour, green tea, and coffee tended to attract the beetles. Ovipositional activity of beetle was higher on the food materials than on nonfood materials. The highest ovipositional activity was observed on coffee, followed by cocoa. Ovipositional activity on black tea, unpolished rice, and green tea was also relatively high. Methanol extracts of coffee beans showed oviposition-stimulatory activity. Therefore, the high ovipositional activity observed on coffee beans could be attributed to oviposition stimulants contained in the beans. In the egg-to-adult survival test, all eggs laid on polished rice or tobacco leaves developed successfully into adults, whereas none of the eggs laid on black tea, green tea, or coffee beans developed into adults. These findings suggest that suitability as an attractive target, suitability as an oviposition site, and suitability as larval food are not always compatible.     

Experimental chronic pulmonary infection in mice caused by Klebsiella pneumoniae

Examination of mouse strain differences in susceptibility to experimental respiratory tract infection with Klebsiella pneumoniae 27 revealed that a chronic pulmonary infection model could be established using CBA/J mice. After 6 X 10(5) colony-forming units of K. pneumoniae 27 were inoculated into the lung, the bacterial counts in the lungs changed with time showing four different phases: initial decrease, regrowth, steady-state, and final increase leading to death. Throughout the course of the infection, the challenge bacteria were isolated mainly from the respiratory organs. Pulmonary gross lesions appeared on day 2 after infection and persisted thereafter. Lobar consolidation was the primary lesion and occurred mainly in the anterior and middle lobes of the right lung, and the median lobe. Mice began to die from 4 weeks after aerosol exposure. This model may be useful for investigating the pathogenesis of chronic pulmonary infection by Klebsiella and its therapy.     

Protective effect of recombinant human interleukin-2 against lethal infection caused by Klebsiella pneumoniae

The effects of recombinant human interleukin-2 (rIL-2) administered prophylactically on the death of CBA/J mice challenged with Klebsiella pneumoniae 27 intraperitoneally were examined. rIL-2 administered subcutaneously at 20 micrograms per mouse for 7 days enhanced survival after a lethal challenge. The injection of anti-asialo GM1 antibody did not influence the effect of rIL-2. In mice given rIL-2, the number of peritoneal macrophages increased, and the infiltration of polymorphonuclear leukocytes (PMN) into the peritoneal cavity after the bacterial challenge was enhanced. In addition, adoptive transfer of sera and peritoneal exudate cells (PEC), consisting of an approximately equal number of macrophages and PMN, obtained from mice given rIL-2 enhanced resistance to a K. pneumoniae infection, compared with adoptive transfer of sera and PEC obtained from mice not given rIL-2. These results indicate that rIL-2 protects mice from a lethal challenge with K. pneumoniae, and suggest that the protective effect is due to an increase in the number of phagocytic cells and in the cooperative activity of the sera and the phagocytic cells.