Tricyclic-Carbocyclic RORγt Inverse Agonists-Discovery of BMS-986313.

SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.

Biological profiling of novel tricyclic inhibitors of bacterial DNA gyrase and topoisomerase IV.

OBJECTIVES: The objective of this study was to characterize the in vitro and in vivo biological properties of a novel series of small-molecule bacterial type IIA topoisomerase inhibitors. METHODS: Bacterial susceptibility testing was performed by broth microdilution. Resistance frequencies were determined by plating bacteria onto agar containing test compound and enumerating mutants. Bacteria were passaged using subinhibitory concentrations of antibacterials to generate resistance. Target enzyme inhibition was determined by exposure to antibacterials and DNA; topoisomers were visualized by gel electrophoresis. Oral and intravenous pharmacokinetic profiles were determined in mice. In vivo efficacy was determined using a mouse model of septicaemia and thigh infection with MSSA and MRSA, respectively. RESULTS: Representative compounds REDX04139, REDX05604 and REDX05931 demonstrated in vitro potency against a range of Gram-positive and fastidious Gram-negative pathogens. Clinical isolate testing revealed REDX04139 and REDX05931 had MIC90 values of 0.25 and 0.5 mg/L, respectively, for MRSA and MIC90 values of 2 mg/L for streptococci. REDX04139 was bactericidal in vitro against Staphylococcus aureus at 8× MIC over 6 h. Pharmacokinetic profiling of REDX04139 and REDX05604 in mice revealed low clearance and excellent bioavailability (≥71%). REDX04139 provided 100% survival against S. aureus in a mouse septicaemia model, while REDX05604 reduced bacterial load by up to 3.7 log units in the MRSA mouse thigh infection model. CONCLUSIONS: Redx Pharma has discovered a novel series of topoisomerase inhibitors that are being further developed for drug-resistant bacteria.

Fragrance material review on methyl-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl ketone.

A toxicologic and dermatologic review of methyl 2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl ketone when used as a fragrance ingredient is presented. Methyl 2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl ketone is a member of the fragrance structural group Alkyl Cyclic Ketones. These fragrances can be described as being composed of an alkyl, R1, and various substituted and bicyclic saturated or unsaturated cyclic hydrocarbons, R2, in which one of the rings may include up to 12 carbons. Alternatively, R2 may be a carbon bridge of C2-C4 carbon chain length between the ketone and cyclic hydrocarbon. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for methyl 2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl ketone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, repeated dose, and genotoxicity data. A safety assessment of the entire Alkyl Cyclic Ketones will be published simultaneously with this document; please refer to Belsito et al. (Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2013. A Toxicologic and Dermatologic Assessment of Alkyl Cyclic Ketones When Used as Fragrance Ingredients (submitted for publication)) for an overall assessment of the safe use of this material and all Alkyl Cyclic Ketones in fragrances.

Cyclic volatile methylsiloxane bioaccumulation in flounder and ragworm in the Humber Estuary.

Cyclic volatile methylsiloxanes are being subjected to regulatory scrutiny as possible PBT chemicals. The investigation of bioaccumulation has yielded apparently contradictory results, with high laboratory fish bioconcentration factors on the one hand and low field trophic magnification factors on the other. In this study, octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6) were studied along with polychlorinated biphenyls (PCBs) in sediments, ragworm, and flounder from six sites in the Humber Estuary. Bioaccumulation was evaluated using multimedia bioaccumulation factors (mmBAFs) which quantified the fraction of the contaminant present in the aquatic environment that is transferred to the biota. PCB 180, a known strongly bioaccumulative chemical, was used as a benchmark. The mean mmBAF of D5 was about twice that of PCB 180 in both polycheates and flounder, while for D4 it was 6 and 14 times higher, respectively. The mmBAF of D6 was a factor 5-10 lower than that of PCB180. The comparatively strong multimedia bioaccumulation of D4 and D5, even in the absence of biomagnification, was explained by both compounds having a >100 times stronger tendency to partition into lipid rather than into organic carbon, while PCB 180 partitions to a similar extent into both matrices.

A toxicologic and dermatologic assessment of cyclic acetates when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

Fragrance material review on 4-methyl-8-methylenetricyclo[3.3.1.(3,7)]decan-2-yl acetate.

A toxicologic and dermatologic review of 4-methyl-8-methylenetricyclo[3.3.1.(3,7)]decan-2-yl acetate when used as a fragrance ingredient is presented.

Fragrance material review on decahydro-beta-naphthyl acetate.

A toxicologic and dermatologic review of decahydro-beta-naphthyl acetate when used as a fragrance ingredient is presented.

Acute toxicity of gymnodimine to mice.

The acute toxicity of the phycotoxin gymnodimine to female Swiss mice by intraperitoneal injection and by oral administration has been determined. Gymnodimine was highly toxic by injection, the LD50 being only 96 microg/kg. Animals either died within 10 min of injection or made a full recovery with no perceptible long-term effects. Gymnodimine was also toxic after oral administration by gavage (LD50 755 microg/kg), but was much less toxic when administered with food. No signs of toxicity were seen in mice voluntarily ingesting food containing gymnodimine at a level sufficient to give a dose of approximately 7500 microg/kg. Pre-treatment with physostigmine or neostigmine protected against injected gymnodimine, suggesting that the latter exerts its toxic effects via blockade of nicotinic receptors at the neuromuscular junction. The low toxicity of gymnodimine when ingested with food suggests that this compound is of low risk to humans, a conclusion that is consonant with anecdotal evidence for the absence of harmful effects in individuals consuming shellfish contaminated with gymnodimine.

Effect of polycyclic aromatic hydrocarbons on the elimination kinetics of pyrene and the urinary excretion profile of 1-hydroxypyrene in the rat.

Pyrene was chosen as a noncarcinogen model of polycyclic aromatic hydrocarbons (PAHs). Groups of male Wistar rats were dosed with pyrene and with mixture of pyrene and fluoranthene, pyrene and benz[a]anthracene, or pyrene, fluoranthene, and benz[a]anthracene at 20 mg/kg by intravenous or oral routes. Blood samples were taken at 0.25, 0.5, 1, 2, 3, 4, and 5 h after administration. The concentration of pyrene was determined by gas chromatography. The toxicokinetic parameters for pyrene were determined from the time course of blood concentration. A significant increase in the bioavailability of pyrene after treatment with other PAHs was observed. Urinary 1-hydroxypyrene excretion was analyzed after pretreatment with acenaphthene, naphthalene, chrysene, phenanthrene, benz[a]anthracene, and benzo[a]pyrene. The urine from rats was collected for 3 d and the concentration of 1-hydroxypyrene was determined using high-performance liquid chromatography (HPLC). Most compounds examined caused a decrease in the urinary excretion of the metabolite of pyrene.