A novel series of benzimidazole NR2B-selective NMDA receptor antagonists.

A series of novel benzimidazoles are discussed as NR2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists. High throughput screening (HTS) efforts identified a number of potent and selective NR2B antagonists such as 1. Exploration of the substituents around the core of this template identified a number of compounds with high potency for NR2B (pIC(50) >7) and good selectivity against the NR2A subunit (pIC(50) <4.3) as defined by FLIPR-Ca(2+) and radioligand binding studies. These agents offer potential for the development of therapeutics for a range of nervous system disorders including chronic pain, neurodegeneration, migraine and major depression.

3,5-Disubstituted-indole-7-carboxamides: the discovery of a novel series of potent, selective inhibitors of IKK-ß.

The discovery and hit-to-lead exploration of a novel series of selective IKK-ß kinase inhibitors is described. The initial lead fragment 3 was identified by pharmacophore-directed virtual screening. Homology model-driven SAR exploration of the template led to potent inhibitors, such as 12, which demonstrate efficacy in cellular assays and possess encouraging developability profiles.

Effect of the protease plasmin on C. elegans hyperactive DEG/ENaC channels MEC-4(d) and UNC-8(d).

C. elegans MEC-4 and UNC-8 belong to the DEG/ENaC family of voltage-independent Na+ channels and have been implicated in mechanosensation and synaptic remodeling. MEC-4 and UNC-8 hyperactive mutants, designated (d) mutants, conduct enhanced currents and cause cell death due to uncontrolled influx of cations. We show here that MEC-4(d) but not UNC-8(d) currents are further potentiated by treatment with the protease plasmin and that this effect is dependent upon co-expression with the chaperon protein MEC-6. Mammalian DEG/ENaC channels are cleaved by plasmin in the channel finger domain and both MEC-4 and UNC-8 have a predicted plasmin cleavage site in this domain. We previously showed that MEC-4(d), but not UNC-8(d), currents are increased by co-expression with MEC-6, which interacts with the channel via the finger domain. We suggest that interaction of the channel subunit with MEC-6 may render the plasmin cleavage site more accessible. Given that C. elegans expresses a homolog of plasmin, these effects might be relevant in vivo.

The discovery and initial optimisation of pyrrole-2-carboxamides as inhibitors of p38alpha MAP kinase.

A novel pyrrole-2-carboxamide series of p38alpha inhibitors, discovered through the application of virtual screening, is presented. Following evaluation of activity, selectivity and developability properties of commercially available analogues, a synthesis program enabled rapid assessment of the series' suitability for further lead optimisation studies.

Out-of-hospital chest escharotomy: a case series and procedure review.

Initial care for the burned trauma patient focuses on the rapid assessment and stabilization of airway, breathing, and circulation. Circumferential chest burns may restrict respiratory effort and inhibit adequate ventilation. When this occurs, chest escharotomy is the recommended treatment to restore chest expansion and therefore ventilation. Emergency medical services (EMS) providers infrequently encounter patients with circumferential chest burns, and escharotomy is generally not included in their scope of practice. The authors could not locate any documentation of other escharotomies performed in the out-of-hospital setting. This case series describes the care of two patients that required out-of-hospital chest escharotomy by physician members of a helicopter medical crew. The procedures of chest and neck escharotomies are reviewed, and the logistics of performing escharotomy in the prehospital setting are described.

9,10-Dioxa-1,2-diaza-anthracene derivatives from tetrafluoropyridazine.

Reaction of tetrafluoropyridazine with catechol gives a tricyclic 9,10-dioxa-1,2-diaza-anthracene system by a sequential nucleophilic aromatic substitution ring annelation process, further extending the use of perfluoroheteroaromatic derivatives for the synthesis of unusual polyfunctional heterocyclic architectures. The tricyclic scaffold reacts with amines and sodium ethoxide providing a short series of functional 9,10-dioxa-1,2-diaza-anthracene systems.

Selective activation of the SK1 subtype of human small-conductance Ca2+-activated K+ channels by 4-(2-methoxyphenylcarbamoyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (GW542573X) is dependent on serine 293 in the S5 segment.

A new small molecule, 4-(2-methoxy-phenylcarbamoyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (GW542573X), is presented as an activator of small-conductance Ca(2+)-activated K(+) (SK, K(Ca)2) channels and distinguished from previously published positive modulators of SK channels, such as 1-ethyl-2-benzimidazolinone (1-EBIO) and cyclohexyl-[2-(3,5-dimethylpyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), in several aspects. GW542573X is the first SK1-selective compound described: an EC(50) value of 8.2 +/- 0.8 microM (n = 6, [Ca(2+)](i) = 200 nM) was obtained from inside-out patches excised from hSK1-expressing HEK293 cells. Whole-cell experiments showed that hSK2 and hSK3 channels were more than 10 times, and hIK channels even more than 100 times, less sensitive to GW542573X. The Ca(2+)-response curve of hSK1 was left-shifted from an EC(50)(Ca(2+)) value of 410 +/- 20 nM (n = 9) to 240 +/- 10 nM (n = 5) in the presence of 10 microM GW542573X. In addition to this positive modulation, GW542573X activated SK1 in the absence of Ca(2+) and furthermore induced a 15% increase in the maximal current at saturating Ca(2+). Thus, GW542573X also acts as a genuine opener of the hSK1 channels, a mechanism of action (MOA) not previously obtained with SK channels. The differential potency on hSK1 and hSK3 enabled a chimera approach to elucidate site(s) important for this new MOA and selectivity property. A single amino acid (Ser293) located in S5 of hSK1 was essential, and substituting the corresponding Leu476 in hSK3 with serine conferred hSK1-like potency (EC(50) = 9.3 +/- 1.4 microM, n = 5). GW542573X may activate SK channels via interaction with "deep-pore" gating structures at the inner pore vestibule or the selectivity filter in contrast to 1-EBIO and CyPPA that exert positive modulation via the intracellular calmodulin binding domain.

Polysubstituted pyridazinones from sequential nucleophilic substitution reactions of tetrafluoropyridazine.

4,5,6-trifluoropyridazin-3(2H)-one can be used as a scaffold for the synthesis of various 4,5- and 4,6-disubstituted and ring-fused pyridazinone systems by sequential nucleophilic aromatic substitution processes. Although the regioselectivity of nucleophilic substitution can be affected by the nature of the nucleophile and the substituent attached to the pyridazinone ring, a variety of polyfunctional systems can be readily accessed by sequential nucleophilic substitution methodology which may have applications in the drug discovery arena. For example, reaction of 4,5,6-trifluoropyridazin-3(2H)-one with nitrogen nucleophiles leads to a mixture of aminated products arising from substitution of fluorine located at the 4- and 5-positions. The ratio of isomers obtained depends on the nucleophile where the 4-isomer is the major product for reaction with primary and secondary amines such as butylamine, morpholine, and aniline derivatives. Subsequent reaction of representative 4-aminated products gave 4,5-disubstituted systems and ring fused derivatives may be formed by reaction of 4,5,6-trifluoropyridazin-3(2H)-one or 4-substituted systems with N,N'-dimethylethylenediamine.

Perhalogenated pyrimidine scaffolds. Reactions of 5-chloro-2,4,6-trifluoropyrimidine with nitrogen centred nucleophiles.

BACKGROUND: Highly functionalised pyrimidine derivatives are of great importance to the life-science industries and there exists a need for efficient synthetic methodology that allows the synthesis of polysubstituted pyrimidine derivatives that are regioselective in all stages to meet the demands of RAS techniques for applications in parallel synthesis. 5-Chloro-2,4,6-trifluoropyrimidine may be used as a scaffold for the synthesis of polyfunctional pyrimidine systems if sequential nucleophilic aromatic substitution processes are regioselective. RESULTS: Use of 5-chloro-2,4,6-trifluoropyrimidine as a core scaffold for the synthesis of functionalised pyrimidine systems is assessed in reactions with a small range of nitrogen centred nucleophiles. Mixtures of products arising from nucleophilic aromatic substitution processes are formed, reflecting the activating effect of ring nitrogen and the steric influences of the chlorine atom. CONCLUSIONS: 5-Chloro-2,4,6-trifluoropyrimidine is not an ideal scaffold for analogue synthesis or for multiple substitution processes because purification must be performed to remove the 2-substituted regioisomer from the mixture before further reactions can be carried out. However, 4-amino derivatives can be isolated in acceptable yields using this methodology.

3,5-Disubstituted-indole-7-carboxamides as IKKß Inhibitors: Optimization of Oral Activity via the C3 Substituent.

IκB kinase ß (IKKß or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds 24 and (R)-28 as having robust in vivo activity.

Progress towards the development of anti-inflammatory inhibitors of IKKbeta.

The IkappaB kinases (IKKs) are essential components of the signaling pathway by which the NF-kappaB p50/RelA transcription factor is activated in response to pro-inflammatory stimuli such as lipopolysaccharide (LPS) and tumor necrosis factor (TNFalpha). NF-kappaB signaling results in the expression of numerous genes involved in innate and adaptive immune responses. The pathway is also implicated in chronic inflammatory disorders including rheumatoid arthritis (RA), chronic obstructive pulmonary disorder (COPD), and asthma. Inhibition of the kinase activity of the IKKs is therefore a promising mechanism for intervention in these diseases. Here, we will review the literature describing small molecule inhibitors of IKKbeta (IKK2), the most widely studied of the IKKs.

Discovery of 6-aryl-7-alkoxyisoquinoline inhibitors of IkappaB kinase-beta (IKK-beta).

The identification and progression of a potent and selective series of isoquinoline inhibitors of IkappaB kinase-beta (IKK-beta) are described. Hit-generation chemistry based on IKK-beta active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-alpha.

Feasibility of sternal intraosseous access by emergency medical technician students.

OBJECTIVE: Emergency medical technician-basic (EMT-B) providers are not trained to establish vascular or intraosseous (IO) access on critically ill patients. This study was conducted to examine the feasibility of training EMT-B students to correctly place a commercial sternal IO infusion device (FAST-1). METHODS: Twenty-nine EMT-B students attended a two-hour training session. Subjects were subsequently tested in FAST-1 application using a modified resuscitation mannequin permitting IO needle deployment. Two observers assessed correct IO application and technique. Results were analyzed using descriptive statistics (binomial proportions and medians with 95% confidence intervals). Inter-rater agreement of observations was evaluated using kappa statistics and intraclass correlation coefficients (ICCs). RESULTS: Inter-rater agreement ranged from fair to excellent (kappa = 0.37-1.00) for all parameters except sternal notch identification (kappa = -0.03). Reliabilities of elapsed times were good (ICC = 0.83, 0.31). Correct identification of the sternal notch was accomplished by 28 of 29 students (96.6%; 95% CI: 82.2-99.9%). Correct application of the IO target patch was achieved by 29 of 29 (100.0%; 88.1-100.0%). First-attempt successful IO needle deployment was achieved by 16 of 29 (55.2%; 35.7-73.6%). Overall successful IO needle deployment within four attempts was achieved by 27 of 29 (93.1%; 77.2-99.2%). The protective dome was correctly applied by 27 of 29 (93.1%; 77.2-99.2%). The median time to needle deployment was 27.5 seconds (95% CI: 24-31). The median time to dome placement was 50 seconds (95% CI: 42-55). CONCLUSIONS: EMT-B students with minimal training demonstrated limited success with applying a commercial sternal IO device. Clinical application by EMT-Bs on critically ill patients may be possible with more intensive training.

Combined application of organozinc chemistry and one-pot hydroboration-Suzuki coupling to the synthesis of amino acids.

Hydroboration using 9-BBN-H of the protected enantiomerically pure but-3-enylglycine derivative 11, prepared by copper-catalysed allylation of the serine-derived organozinc reagent 1, followed by Suzuki coupling of the derived borane with a variety of aromatic halides, 2-bromopyridine and 2-bromopropene gives the protected amino acids 14a-l and 15. This method augments our previous methods for the synthesis of phenylalanine homologues.