Is ‘activist’ a dirty word? Place identity, activism and unconventional gas development across three continents

Communities respond to unconventional gas in a variety of ways. In some communities, industry has held a social license, while in other areas, industrial development has been slowed, halted, or prevented by social resistance. Repeatedly, across multiple nations and communities, we have observed that social identities that either incorporate or eschew activism intersect with perceptions of this development's effect on place identity to either foster or discourage opposition. Particularly interesting are cases in which fracking is perceived to threaten local place identity, but where activism conflicts with social identity. To mobilise different sectors of the population, it often appears important for local residents to be perceived as ‘regular citizens’ and not as activists. We explore how intersection of social identities and place identity shaped the different ways in which communities in Australia, Canada, the Netherlands, and the United States have responded to unconventional gas development. Communities resisting development often see ‘activism’ as something that ‘outsiders’ do and that must be rejected as insufficiently objective and neutral. This view of activism and activists produces specific forms of resistance that differ from typical ‘activist’ actions, in which ‘knowledge’, ‘information’, neutrality, and objectivity are particularly important.</p

Discovery of 9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one (GLPG1205), a unique GPR84 negative allosteric modulator undergoing evaluation in a phase II clinical trial

GPR84 is a medium chain free fatty acid-binding G-protein-coupled receptor associated with inflammatory and fibrotic diseases. As the only reported antagonist of GPR84 (PBI-4050) that displays relatively low potency and selectivity, a clear need exists for an improved modulator. Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, led to the identification of potent and selective GPR84 inhibitor GLPG1205 (36). Compared with the initial hit, 36 showed improved potency in a guanosine 5′-O-[γ-thio]triphosphate assay, exhibited metabolic stability, and lacked activity against phosphodiesterase-4. This novel pharmacological tool allowed investigation of the therapeutic potential of GPR84 inhibition. At once-daily doses of 3 and 10 mg/kg, GLPG1205 reduced disease activity index score and neutrophil infiltration in a mouse dextran sodium sulfate-induced chronic inflammatory bowel disease model, with efficacy similar to positive-control compound sulfasalazine. The drug discovery steps leading to GLPG1205 identification, currently under phase II clinical investigation, are described herein

Diversity-oriented synthesis of furo[3,2-f]chromanes with antimycobacterial activity

International audienceWe previously reported the synthesis and the antimycobacterial activity of 4-(7,7-dimethyl-7H-furo[3,2-f]chromen-2-yl)pyridine. From this result, we sought to design simple synthetic accesses to related structures allowing the preparation of a diverse set of analogues. Two approaches were investigated. From 3-(2-bromo-7,7-dimethyl-8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)propyl acetate, we prepared 2-arylated derivatives via Suzuki-Miyaura reactions between this bromine-bearing compound and various arylboronates. Moreover, and even more simple, we prepared the ((6-hydroxy-2,2,7,8-tetramethylchroman-5-yl)methyl)triphenylphosphonium salt via a selective bromination of 2,2,5,7,8-pentamethylchroman-6-ol. From this salt, a two stage Wittig reaction with an array of activated acids allowed the quick preparation of many analogues. The biological evaluation of the effect of these compounds on the growth of Mycobacterium bovis as well as Mycobacterium tuberculosis pointed out a fourfold improvement of the antimycobacterial properties for one of the compounds made. However, the many analogues which inhibited the growth of M. tuberculosis in the 0.6-5 microg/mL range turned out to be also cytotoxic on VERO cells growth at the same concentration rang

A new synthetic access to furo[3,2-f]chromene analogues of an antimycobacterial.

International audienceFrom the structure of 3,3-dimethyl-3H-benzofuro[3,2-f][1]-benzopyran, a selective in vitro inhibitor of mycobacterial growth, we have undertaken a structure-activity relationship investigation. We wish to report here our results on the use of [2+3] cycloadditions between 2-formylbenzoquinone and various enol derivatives to give various 4-formyl-5-hydroxy benzofurans. In the next step, an ytterbium triflate-catalysed reaction with 2-methylpropene allowed the preparation of various original furo[3,2-f]chromenes derivatives. Their biological evaluation on the growth of Mycobacterium smegmatis as well as Mycobacterium tuberculosis pointed out that some analogues were four times more active than the initial hit

A new synthetic access to furo[3,2-f]chromene analogues of an antimycobacterial

From the structure of 3,3-dimethyl-3H-benzofuro[3,2-f][1]-benzopyran, a selective in vitro inhibitor of mycobacterial growth, we have undertaken a structure-activity relationship investigation. We wish to report here our results on the use of [2+3] cycloadditions between 2-formylbenzoquinone and various enol derivatives to give various 4-formyl-5-hydroxy benzofurans. In the next step, an ytterbium triflate-catalysed reaction with 2-methylpropene allowed the preparation of various original furo[3,2-f]chromenes derivatives. Their biological evaluation on the growth of Mycobacterium smegmatis as well as Mycobacterium tuberculosis pointed out that some analogues were four times more active than the initial hit

Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases: Particular potency of 1H-indazole-7-carbonitrile

A series of new 7-monosubstituted and 3,7-disubstituted indazoles have been prepared and evaluated as inhibitors of nitric oxide synthases (NOS). 1H-Indazole-7-carbonitrile (6) was found equipotent to 7-nitro-1H-indazole (1) and demonstrated preference for constitutive NOS over inducible NOS. By contrast, 1H-indazole-7-carboxamide (8) was slightly less potent but demonstrated a surprising selectivity for the neuronal NOS. Further substitution of 6 by a Br-atom at carbon-3 of the heterocycle enhanced 10-fold the inhibitory effects. Inhibition of NO formation by 6 appeared to be competitive versus both substrate and the cofactor (6R)-5,6,7,8-tetrahydro-L L-biopterin (H 4 B). In close analogies with 1, compound 6 strongly inhibited the NADPH oxi-dase activity of nNOS and induced a spin state transition of the heme-Fe III. Our results are explained with the help of the X-ray structures that identified key-features for binding of 1 at the active site of NOS

Identification of a 4‑(Hydroxymethyl)diarylhydantoin as a Selective Androgen Receptor Modulator

Structural modification performed on a 4-methyl-4-(4-hydroxyphenyl)­hydantoin series is described which resulted in the development of a new series of 4-(hydroxymethyl)­diarylhydantoin analogues as potent, partial agonists of the human androgen receptor. This led to the identification of (<i>S</i>)-(−)-4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)­benzonitrile ((<i>S</i>)-(−)-<b>18a</b>, GLPG0492) evaluated in vivo in a classical model of orchidectomized rat. In this model, (−)-<b>18a</b> exhibited anabolic activity on muscle, strongly dissociated from the androgenic activity on prostate after oral dosing. (−)-<b>18a</b> has very good pharmacokinetic properties, including bioavailability in rat (<i>F</i> > 50%), and is currently under evaluation in phase I clinical trials