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IntroductionThe history of leukotriene (LT) research has been documented in numerous articles and reviews since the discovery of the LT biosynthetic pathway 1 and the delineation of the various chemical structures involved in the pathway and their total synthesis. 2 Three previous Perspective articles have provided periodic updates, the first in 1981, 3 the second 1 decade later covering LT receptor antagonists, 4 and the third in 1992 covering LT biosynthesis inhibitors. 5 With this background, the task of this Perspective is to update the status of LT intervention research by providing an overview of the leading enzyme inhibitors and receptor antagonists as well as the status of clinical trials with these agents and how the latter are influencing the development of new therapeutic modalities for the treatment of inflammation and allergy.The clinical proof-of-concept for LT intervention has taken longer than expected considering that the biosynthesis and chemical composition of LTs were delineated by 1979. It is now clear that LT intervention therapy represents a promising new modality for the treatment of asthma. Several compounds including the 5-lipoxygenase (5-LO) inhibitor zileuton (1) and the cysteinyl LT antagonist zafirlukast (2) have completed pivotal clinical trials, while several other LT modulators are progressing to this stage. Within a few years the therapeutic potential of these new agents in asthma and other inflammatory and allergic disorders will be evident. Leukotriene Intervention StrategiesLeukotriene Biosynthesis. Leukotrienes are biosynthesized via the 5-LO (arachidonate:oxygen 5-oxidoreductase, EC 1.13.11.34) pathway of arachidonic acid (AA) metabolism ( Figure 1). The 5-LO product LTA 4 is a pivotal reactive epoxide intermediate in an important branch in the biosynthetic pathway that is further metabolized by either (i) stereoselective hydration by LTA 4 hydrolase to LTB 4 or (ii) glutathione addition by LTC 4 synthase to LTC 4 . Successive amino acid cleavage steps convert LTC 4 to LTD 4 and then to LTE 4 . The cysteinyl LTs (LTC 4 , LTD 4 , LTE 4 ) are the constituents of the biological substance previously known as slowreacting substance of anaphlyaxis (SRS-A). 6 LTB 4 is a very potent neutrophil chemotactic agent, inducing neutrophil adherence to endothelial cells, degranulation, and modulation of cytokine production. The biosynthesis, release, and recovery of LTs from specific cells involved in inflammatory disorders together with the observed ability of these products to mimic aspects of disease support their involvement as mediators of inflammatory and allergic disorders. 7,8 Despite such circumstantial evidence, confirmation of the pathophysiological role of these mediators requires selective blockade of their actions.At the outset of research efforts in the LT area, it was not entirely clear which LTs or subsequent metabolites were the predominant mediators of a particular human disorder. LTs are short-lived, being rapidly converted to inactive metabolites, and prolonged expressi...

We give an overview and describe the rationale, methods, and first results from NIRCam images of the JWST “Prime Extragalactic Areas for Reionization and Lensing Science” (PEARLS) project. PEARLS uses up to eight NIRCam filters to survey several prime extragalactic survey areas: two fields at the North Ecliptic Pole (NEP); seven gravitationally lensing clusters; two high redshift protoclusters; and the iconic backlit VV 191 galaxy system to map its dust attenuation. PEARLS also includes NIRISS spectra for one of the NEP fields and NIRSpec spectra of two high-redshift quasars. The main goal of PEARLS is to study the epoch of galaxy assembly, active galactic nucleus (AGN) growth, and First Light. Five fields—the JWST NEP Time-Domain Field (TDF), IRAC Dark Field, and three lensing clusters—will be observed in up to four epochs over a year. The cadence and sensitivity of the imaging data are ideally suited to find faint variable objects such as weak AGN, high-redshift supernovae, and cluster caustic transits. Both NEP fields have sightlines through our Galaxy, providing significant numbers of very faint brown dwarfs whose proper motions can be studied. Observations from the first spoke in the NEP TDF are public. This paper presents our first PEARLS observations, their NIRCam data reduction and analysis, our first object catalogs, the 0.9–4.5 μm galaxy counts and Integrated Galaxy Light. We assess the JWST sky brightness in 13 NIRCam filters, yielding our first constraints to diffuse light at 0.9–4.5 μm. PEARLS is designed to be of lasting benefit to the community.

The hydroxamic acid functionality can be incorporated in a variety of simple molecules to produce potent inhibitors of 5-lipoxygenase. As an example of this, the structure-activity relationships in a series of omega-phenylalkyl and omega-naphthylalkyl hydroxamic acids are presented. Among the features described are the influence of hydrophobicity, aryl substitution, and modifications of the hydroxamate group on enzyme inhibitory potency. To assist in the selection of more potent hydroxamic acid inhibitors, a simple hypothesis about the nature of enzyme-inhibitor binding was devised. In this hypothesis, the structures of compounds were matched to a proposed geometry of arachidonic acid when bound to the enzyme. Compounds that match best without extending into disfavored regions were predicted to be the best inhibitors. Three series of hydroxamates selected according to this approach are described. Within these series are some of the most potent inhibitors of 5-lipoxygenase reported to date.

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