Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 Å, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.

The synthesis, antiviral and pharmacokinetic properties of zanamivir (ZMV) dimers 8 and 13 are described. The compounds are highly potent neuraminidase (NA) inhibitors which, along with dimer 3, are being investigated as potential second generation inhaled therapies both for the treatment of influenza and for prophylactic use. They show outstanding activity in a 1 week mouse influenza prophylaxis assay, and compared with ZMV, high concentrations of 8 and 13 are found in rat lung tissue after 1 week. Retention of compounds in rat lung tissue correlated both with molecular weight (excluding 3 and 15) and with a capacity factor K' derived from immobilized artificial membrane (IAM) chromatography (including 3 and 15). Pharmacokinetic parameters for 3, 8 and 13 in rats show the compounds have short to moderate plasma half-lives, low clearances and low volumes of distribution. Dimer 3 shows NA inhibitory activity against N1 viruses including the recent highly pathogenic H5N1 A/Chicken/Vietnam/8/2004. In plaque reduction assays, 3, 8 and 13 show good to outstanding potency against a panel of nine flu A and B virus strains. Consistent with its shorter and more rigid linking group, dimer 8 has been successfully crystallized.

The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.

Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a is a partial agonist while 9e and 15a are micromolar antagonists in a mouse mammary tumor virus transactivation assay.

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The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFkappaB agonism with pIC50 of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFkappaB agonism with pIC50 of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC50 of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.

BW245C analogues which have 15'-keto, -oximino, -sulphinyl, -sulphonyl, -methyl, -1-adamantyl, 14'-hydroxy, 16'-hydroxy, 13'-14'-NH=CH, -NH-CH2, or -NH-CO groups have been synthesized and evaluated for their activity in inhibiting platelet aggregation and for their cardiovascular actions: the 13'-aza analogues 13 and 14 are more potent inhibitors of human platelet aggregation than BW245C (0.3, 0.6 and 0.2 x PGI2, respectively) and these inhibitory activities on platelet aggregation increase on incubation in vitro. The prostaglandin mimetic properties of 13 (BW68C) and 14 (BW361C) were studied in more detail and their platelet inhibitory and vasodilatory effects found to be of longer duration than those of BW245C. All other modifications to the omega-chain of BW245C led to less potent or inactive compounds.

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