Epidemic hemorrhagic fever in Hubei Province, The People's Republic of China: a clinical and serological study

Between July 1975 and April 1980, 71 patients were admitted to the Second Attached Hospital of Hubei Provincial Medical College in Wuchang with the diagnosis of epidemic hemorrhagic fever (EHF). The clinical course among these patients was similar to that described for patients with Korean hemorrhagic fever, and hemorrhagic fever with renal syndrome of the U.S.S.R. The overall mortality was 11.2 percent. Sera obtained from some of these patients as well as from patients admitted to the First Attached Hospital of Hubei Provincial Medical College were tested against an antigen associated with Korean hemorrhagic fever and showed exceedingly high antibody titers. We conclude that EHF in Central China represents the same or a closely related disease process as Korean hemorrhagic fever.     

N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists

A new class of potent NK3R antagonists based on the N',2-diphenylquinoline-4-carbohydrazide core is described. In an ex vivo assay in gerbil, the lead compound 2g occupies receptors within the CNS following oral dosing (Occ(90) 30 mg/kg po; plasma Occ(90) 0.95 microM) and has good selectivity and promising PK properties.     

Impairment of hepatitis B virus virion secretion by single-amino-acid substitutions in the small envelope protein and rescue by a novel glycosylation site

Mutations in the S region of the hepatitis B virus (HBV) envelope gene are associated with immune escape, occult infection, and resistance to therapy. We previously identified naturally occurring mutations in the S gene that alter HBV virion secretion. Here we used transcomplementation assay to confirm that the I110M, G119E, and R169P mutations in the S domain of viral envelope proteins impair virion secretion and that an M133T mutation rescues virion secretion of the I110M and G119E mutants. The G119E mutation impaired detection of secreted hepatitis B surface antigen (HBsAg), suggesting immune escape. The R169P mutant protein is defective in HBsAg secretion as well and has a dominant negative effect when it is coexpressed with wild-type envelope proteins. Although the S domain is present in all three envelope proteins, the I110M, G119E, and R169P mutations impair virion secretion through the small envelope protein. Conversely, coexpression of just the small envelope protein of the M133T mutant could rescue virion secretion. The M133T mutation could also overcome the secretion defect caused by the G145R immune-escape mutation or mutation at N146, the site of N-linked glycosylation. In fact, the M133T mutation creates a novel N-linked glycosylation site ((131)NST(133)). Destroying this site by N131Q/T mutation or preventing glycosylation by tunicamycin treatment of transfected cells abrogated the effect of the M133T mutation. Our findings demonstrate that N-linked glycosylation of HBV envelope proteins is critical for virion secretion and that the secretion defect caused by mutations in the S protein can be rescued by an extra glycosylation site.     

N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II

Introduction of selected amine containing side chains into the 3-position of N',2-diphenylquinoline-4-carbohydrazide based NK3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI(Kr) affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ(90) 7 mg/kg po; plasma Occ(90) 0.4 microM) and has good selectivity and excellent PK properties.     

ACYL GROUP COMPOSITION OF METABOLICALLY ACTIVE LIPIDS IN BRAIN: VARIANCES AMONG SUBCELLULAR FRACTIONS AND DURING POSTNATAL DEVELOPMENT

Using a combination of preparative TLC and GLC technique, the content and acyl group composition of diacyl-glycerophosphoinositols, diacyl-glycerophosphates, diacylglycerols and triacyl-glycerols in brain tissue were determined. The level of diacyl-glycerophosphoinositols in 40 day-old mouse brain was 2.7 μmol/g tissue as compared to 40–170 nmol/g for other minor lipids. The acyl groups of diacyl-glycerophosphoinositols were enriched in 18:0 and 20:4 (n-6). This characteristic acyl group profile was found in microsomes, synaptosomes, and in myelin. The acyl groups of diacyl-glycerophosphates and diacylglycerols were comprised mainly of 16:0, 18:0, 18:1 and 20:4 (n-6). In rat brain subcellular fractions, the acyl groups of diacylglycerols and diacyl-glycerophosphates in the microsomal fraction had a higher proportion of 22:6 (n-3) than those in the myelin and synaptosomal fractions. The acyl groups of the myelin lipids were higher in 18:l and lower in 20:4 (n-6) as compared to those in the microsomal and synaptosomal fractions. The triacylglycerols in brain exhibited an unusual acyl group profile which included small proportions of 14:0, 16:1, 20:4 (n-6), 22:4 (n-6) and 22:6 (n-3). Except for an increase in 18:1 and a corresponding decrease in 16:0 which was found in diacyl-glycerophosphoinositols, no apparent acyl group change was observed in other metabolically active lipids during postnatal brain development.     

Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment

Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.