The synthesis of several pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine analogs is described with one such analog possessing subnanomolar potency in both genotype 1a and 1b cell culture HCV replicon assays.

The ectodomain of HIV-1 gp41 mediates the fusion of viral and host cellular membranes. The peptide-based drug Enfuvirtide1 is precedent that antagonists of this fusion activity may act as anti HIV-agents. Here, NMR screening was used to discover non-peptide leads against this target and resulted in the discovery of a new benzamide 1 series. This series is non-peptide, low molecular weight, and analogs have activity in a cell fusion assay with EC50 values ranging 3–41μM. Structural work on the gp41/benzamide 1 complex was determined by NMR spectroscopy using a designed model peptide system that mimics an open pocket of the fusogenic form of the protein.

ABSTRACT A-315675 is a novel, pyrrolidine-based compound that was evaluated in this study for its ability to inhibit A and B strain influenza virus neuraminidases in enzyme assays and influenza virus replication in cell culture. A-315675 effectively inhibited influenza A N1, N2, and N9 and B strain neuraminidases with inhibitor constant (Ki) values between 0.024 and 0.31 nM. These values were comparable to or lower than the Ki values measured for oseltamivir carboxylate (GS4071), zanamivir, and BCX-1812, except for the N1 enzymes that were found to be the most sensitive to BCX-1812. The time-dependent inhibition of neuraminidase catalytic activity observed with A-315675 is likely due to its very low rate of dissociation from the active site of neuraminidase. The half times for dissociation of A-315675 from B/Memphis/3/89 and A/Tokyo/3/67 (H3N2) influenza virus neuraminidases of 10 to 12 h are significantly slower than the half times measured for oseltamivir carboxylate (33 to 60 min). A-315675 inhibited the replication of several laboratory strains of influenza virus in cell culture with potencies that were comparable or superior to those for oseltamivir carboxylate and BCX-1812, except for the A/H1N1 viruses that were found to be two- to fourfold more susceptible to BCX-1812. A-315675 and oseltamivir carboxylate exhibited comparable potencies against a panel of A/H1N1 and A/H3N2 influenza virus clinical isolates, but A-315675 was found to be significantly more potent than oseltamivir carboxylate against the B strain isolates. The favorable in vitro results relative to other clinically effective agents provide strong support for the further investigation of A-315675 as a potential therapy for influenza virus infections.

ABSTRACT With the recent introduction of neuraminidase (NA) inhibitors into clinical practice for the treatment of influenza virus infections, considerable attention has been focused on the potential for resistance development and cross-resistance between different agents from this class. A-315675 is a novel influenza virus NA inhibitor that has potent enzyme activity and is highly active in cell culture against a variety of strains of influenza A and B viruses. To further assess the therapeutic potential of this compound, in vitro resistance studies have been conducted and a comparative assessment has been made relative to oseltamivir carboxylate. The development of viral resistance to A-315675 was studied by in vitro serial passage of influenza A/N9 virus strains grown in MDCK cells in the presence of increasing concentrations of A-315675. Parallel passaging experiments were conducted with oseltamivir carboxylate, the active form of a currently marketed oral agent for the treatment of influenza virus infections. Passage experiments with A-315675 identified a variant at passage 8 that was 60-fold less susceptible to the compound. Sequencing of the viral population identified an E119D mutation in the NA gene, but no mutations were observed in the hemagglutinin (HA) gene. However, by passage 10 (2.56 μM A-315675), two mutations (R233K, S339P) in the HA gene appeared in addition to the E119D mutation in the NA gene, resulting in a 310-fold-lower susceptibility to A-315675. Further passaging at higher drug concentrations had no effect on the generation of further NA or HA mutations (20.5 μM A-315675). This P15 virus displayed 355-fold-lower susceptibility to A-315675 and >175-fold-lower susceptibility to zanamivir than did wild-type virus, but it retained a high degree of susceptibility to oseltamivir carboxylate. By comparison, virus variants recovered from passaging against oseltamivir carboxylate (passage 14) harbored an E119V mutation and displayed a 6,000-fold-lower susceptibility to oseltamivir carboxylate and a 175-fold-lower susceptibility to zanamivir than did wild-type virus. Interestingly, this mutant still retained susceptibility to A-315675 (42-fold loss). This suggests that cross-resistance between A-315675- and oseltamivir carboxylate-selected variants in vitro is minimal.

Summary..1. A study of individually marked Fulmars during three seasons has shown that both sexes can breed in successive years. The evidence for the theory of intermittent breeding is examined and definitions are given of the various categories of birds which compose the population during the breeding season. It is suggested that the supposed non‐breeding adults which are seen, often in moult, in July are failed‐breeders which have lost their egg or nestling.2. No marked individual changed its nest‐site between years, although the number and identity of sites occupied each July varied considerably.3. No changes of mate occurred among the six marked pairs which nested in two consecutive years.4. There is some evidence that both parents remain near the colony during the week before and after hatching.5. Analysis of the 90 known sites of a colony subject to avian but not wild mammalian predation has revealed a wide range of habitat selection and a strong tendency toward close concentration of nests.6. There is some evidence that the breeding season, as measured by date of hatching, varies from year to year.

Annals of Applied BiologyVolume 29, Issue 1 p. 43-55 THE GREY FIELD SLUG AGRIOLIMAX AGRESTIS L., AND ITS ENVIRONMENT Robert Carrick B.Sc., Ph.D., Robert Carrick B.Sc., Ph.D. Department of Agricultural and Forest Zoology, University of Edinburgh (now Department of Ágricultural Zoology, University of LeedsSearch for more papers by this author Robert Carrick B.Sc., Ph.D., Robert Carrick B.Sc., Ph.D. Department of Agricultural and Forest Zoology, University of Edinburgh (now Department of Ágricultural Zoology, University of LeedsSearch for more papers by this author First published: February 1942 https://doi.org/10.1111/j.1744-7348.1942.tb06920.xCitations: 31AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume29, Issue1February 1942Pages 43-55 RelatedInformation

Among Gasteropod Molluscs the life-histories and development of the most highly evolved members, the terrestrial Pulmonates, have been less intensively studied than those of more primitive aquatic forms. This has been due in part to the technical difficulties involved in the permanent preparation of material for study, and in part to the fact that the investigator seeking for primitive features of phyletic interest is more likely to find these among more generalised species of Gasteropods than among those which are obviously adapted, both during the early stages of their development and in adult life, to a habitat far removed from the ancestral one.It is the purpose of this paper to present data bearing upon the life-history of a single species of land Pulmonate, Agriolimax agrestis L., to enlarge upon certain aspects of the embryology of this species, and to demonstrate the structural and functional changes of the larva which have accompanied the transition from an aquatic to a terrestrial breeding habit.

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The material for this work was obtained from the stock of Axolotls which breed in the Zoology Department of Glasgow University. The objection to using captive specimens for cytological work is overridden by the fact that the Axolotl, unlike some other urodeles, breeds readily in captivity, so that the germ-cell cycle can be taken as normal.The reasons for wishing to add yet another account of urodele spermatogenesis to the considerable number already existing are twofold. First, widely different interpretations of a similar process in different species have been put forward, and one of the most recent accounts (Stieve, 1920, on Proteus) is entirely at variance with the usual course of spermatogenesis in urodeles. Second, there has been great discrepancy in the number of chromosomes assigned to this species.