Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity.

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.

Non-steroidal glucocorticoid agonists: the discovery of aryl pyrazoles as A-ring mimetics.

Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.

Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series.

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.

Design and synthesis of new nonsteroidal glucocorticoid modulators through application of an "agreement docking" method.

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.

Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza.

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.

Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at a once-weekly dosing regimen.

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 A, 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.

Development of a novel series of trialkoxyaryl derivatives as specific and competitive antagonists of platelet activating factor.

The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-[2-[(3,4,5-trimethoxybenzoyl)oxy]ethyl]-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-[2-[[4-(hexyloxy)-3,5-dimethoxybenzoyl]oxy]ethyl]-N,N,N- trimethylammonium iodide (3, pKb 5.43).

Synthesis and inhibitory activity on platelet aggregation of 13'-aza and other omega-chain modified BW245C analogues.

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.

Cardiotonic 'C' ring modified isomazole analogues.

Isomazole analogues which have achiral electron withdrawing substituents at the 4'-position and analogues with heterocyclic 'C' rings have been synthesized and evaluated as inotropic agents. It was found that pyridyl could replace phenyl in the 'C' ring without loss of activity. The 4'-methylsulphonyl, -cyano, -carboxamido, and acetyl analogues had similar inotropic potencies to Isomazole whilst displaying superior cardiovascular profiles in in vivo studies.