The nonchelate enforced chiral amide enolates derived from 4-7 react with alkyl iodide and protected a-amino epoxide electrophiles to produce the HIV protease inhibitors 10 and 16-19 with high diastereoselectivity.

In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

Acute pharmacological blockade of central histamine H 3 receptors (H 3 Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] exemplifies such a selective, nonimidazole H 3 R antagonist with high affinity for rat (pK i ϭ 8.9) and human (pK i ϭ 9.5) H 3 Rs. Acute functional blockade of central H 3 Rs was demonstrated by blocking the dipsogenia response to the selective H 3 R agonist (R)-␣-methylhistamine in mice. In cognition studies, acquisition of a five-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1-1.0 mg/kg), a 10-to 150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121 [(4-(3-(4 -furamide], and A-349821 [(4Ј-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone]. Efficacy in this modelwas maintained for 3 to 6 h and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01-0.3 mg/kg) and aged (0.3-1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0 -3.0 mg/kg) and N40 (1.0 -10.0 mg/kg). Furthermore, ABT-239 (1.0 mg/kg) attenuated methamphetamineinduced hyperactivity in mice. In freely moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1-3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimer's disease and schizophrenia.

Candida albicans and Cryptococcus neoformans cause both superficial and disseminated infections in humans.Current antifungal therapies for deep-seated infections are limited to amphotericin B, flucytosine, and azoles. A limitation is that commonly used azoles are fungistatic in vitro and in vivo. Our studies address the mechanisms of antifungal activity of the immunosuppressive drug rapamycin (sirolimus) and its analogs with decreased immunosuppressive activity. C. albicans rbp1/rbp1 mutant strains lacking a homolog of the FK506-rapamycin target protein FKBP12 were found to be viable and resistant to rapamycin and its analogs. Rapamycin and analogs promoted FKBP12 binding to the wild-type Tor1 kinase but not to a rapamycin-resistant Tor1 mutant kinase (S1972R). FKBP12 and TOR mutations conferred resistance to rapamycin and its analogs in C. albicans, C. neoformans, and Saccharomyces cerevisiae. Our findings demonstrate the antifungal activity of rapamycin and rapamycin analogs is mediated via conserved complexes with FKBP12 and Tor kinase homologs in divergent yeasts. Taken together with our observations that rapamycin and its analogs are fungicidal and that spontaneous drug resistance occurs at a low rate, these mechanistic findings support continued investigation of rapamycin analogs as novel antifungal agents.Cryptococcus neoformans and Candida albicans are two common opportunistic fungal pathogens. Current antifungal agents in clinical use include amphotericin B, fluconazole, and flucytosine (29), which have side effects, lack fungicidal activity, or lack activity against emerging resistant mutants (66). Thus, additional antifungal agents are needed.Several new antifungal agents are in development. The candins are 1,3-␤-glucan synthase inhibitors and are potently active against Candida species and Aspergillus fumigatus (23,40,51,52). The pneumocandin caspofungin acetate-MK-0991 is in phase III clinical trials for candida infections and has been approved for refractory aspergillosis. Broad-spectrum triazoles, including voriconazole, posaconazole, and ravuconazole, are being studied in human trials (50). Combination therapy with different antifungal agents may also improve therapy (20,28,62).Rapamycin (sirolimus) is a natural product of the bacterium Streptomyces hygroscopicus originally discovered in a screen for antimicrobial activity against C. albicans and later found to have potent immunosuppressive activity (4, 63). Rapamycin diffuses into the cell and associates with the peptidylprolyl isomerase FKBP12. Rapamycin inhibits FKBP12 enzymatic activity; however, this inhibition is not related to immunosuppressive or antifungal activity. The targets of the FKBP12-rapamycin complex are the TOR kinases. Two TOR proteins, Tor1 and Tor2, have been characterized in the yeasts S. cerevisiae and Schizosaccharomyces pombe, and a single TOR homolog has been identified in C. albicans, C. neoformans, Drosophila melanogaster, and humans (10,18,33,39,49,56,64). The Tor kinase has been functionally conserved from yeast to ...

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Pharmacological blockade of central histamine H 3 receptors (H 3 Rs) enhances cognition in rodents and offers promise for the clinical treatment of neurological disorders. However, many previously characterized H 3 R antagonists are either not selective for H 3 Rs or have potentially significant tolerability issues. Here, we present in vivo behavioral and neurophysiological data for two novel and selective H 3 R antagonists with improved safety indices. (1 mg/kg). Social memory was also significantly enhanced in the adult rat with A-304121 (3, 10 mg/kg) and A-317920 (1, 3 mg/kg) at doses that produced no significant change in electroencephalogram slow-wave amplitude activity. Relative therapeutic indices (TIs) of 30 and 42 were estimated for A-304121 and A-317920, respectively, by comparing doses producing adverse effects in general observation studies with potency in inhibitory avoidance, which were superior to TIs of 8, 10, and 18 observed for the reference antagonists thioperamide, ciproxifan, and GT-2331, respectively. A-304121 and A-317920 represent a series of novel, H 3 R-selective piperazine amides that enhance cognition in vivo, which could offer advantages over existing H 3 R antagonists or cognition-enhancing agents.

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