ABSTRACT
A search for magnetised quark nuggets (MQN) is reported using acoustic signals from hydrophones placed in the Great Salt Lake (GSL) in the USA. No events satisfying the expected signature were seen. This observation allows limits to be set on the flux of MQNs penetrating the Earth's atmosphere and depositing energy in the GSL. The expected signature of the events was âderived from pressure pulses caused by high-explosive cords between the lake surface and bottom at various locations in the GSL. The limits obtained from this search are compared with those obtained from previous searches and are compared to models for the formation of MQNs.
ABSTRACT
Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFkappaB agonist activity was optimised in an iterative process from pIC(50) 7.5 (for 7), to pIC(50) 10.1 (for 38E1). An explanation for the SAR observed based is presented along with a proposed docking of 38E1 into the active site of the glucocorticoid receptor.
Subject(s)
Pyrazoles/chemistry , Receptors, Glucocorticoid/agonists , Catalytic Domain , Cell Line , Computer Simulation , Humans , Indazoles/chemistry , NF-kappa B/metabolism , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
Aryl aminopyrazole amides capped with N-alkylbenzamides 13-16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxyethyl benzamides (e.g., 16e).
Subject(s)
Benzamides/chemical synthesis , Pyrazoles/chemical synthesis , Receptors, Glucocorticoid/agonists , Administration, Oral , Animals , Benzamides/pharmacology , Humans , Hydrophobic and Hydrophilic Interactions , Prednisolone , Pyrazoles/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Receptors, Glucocorticoid/agonists , Tetrahydronaphthalenes/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Binding Sites , Cell Line , Drug Partial Agonism , Humans , Mammary Tumor Virus, Mouse/genetics , Models, Molecular , Molecular Mimicry , NF-kappa B/genetics , Receptors, Glucocorticoid/antagonists & inhibitors , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Transcription, Genetic/drug effects , Transcriptional Activation/drug effectsABSTRACT
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) 8.8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NFkappaB pIC(50) 8.1 (103%), MMTV pEC(50) 7.02 (36%)). The tetrahydronaphthalene moiety can also be replaced with substituted aryls such as 24E1 and 25E1.
Subject(s)
Glucocorticoids/agonists , Pyrazoles/chemistry , Receptors, Glucocorticoid/agonists , Amides/chemistry , Binding Sites , Chemistry, Pharmaceutical/methods , Drug Design , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Stereoisomerism , Steroids/chemistryABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzoxazines/chemical synthesis , Receptors, Glucocorticoid/agonists , Tetrahydronaphthalenes/chemical synthesis , Administration, Topical , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzoxazines/chemistry , Benzoxazines/pharmacology , Binding, Competitive , Cell Line , Dexamethasone/pharmacology , Humans , Hypersensitivity, Delayed/drug therapy , Mice , Models, Molecular , Radioligand Assay , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/genetics , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Transcription, Genetic/drug effects , Transcriptional Activation/drug effectsABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Receptors, Glucocorticoid/agonists , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/chemistry , Tetrahydronaphthalenes/chemical synthesis , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Cell Line , Cell Line, Tumor , Humans , Ligands , Mice , Models, Molecular , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Transcription, Genetic/drug effects , Transcriptional Activation/drug effectsABSTRACT
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.
Subject(s)
Antiviral Agents/chemical synthesis , Influenza A Virus, H5N1 Subtype , Influenza A virus/drug effects , Influenza B virus/drug effects , Neuraminidase/antagonists & inhibitors , Orthomyxoviridae Infections/prevention & control , Sialic Acids/chemistry , Sialic Acids/chemical synthesis , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Cell Line , Crystallization , Dimerization , Guanidines , Influenza A virus/enzymology , Influenza B virus/enzymology , Lung/drug effects , Lung/enzymology , Lung/virology , Male , Membranes, Artificial , Mice , Models, Molecular , Molecular Weight , Orthomyxoviridae Infections/virology , Pyrans , Rats , Rats, Sprague-Dawley , Sialic Acids/pharmacokinetics , Sialic Acids/pharmacology , Stereoisomerism , Viral Plaque Assay , ZanamivirABSTRACT
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.
