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The new and rapid advancement in the complexity of biologics drug discovery has been driven by a deeper understanding of biological systems combined with innovative new therapeutic modalities, paving the way to breakthrough therapies for previously intractable diseases. These exciting times in biomedical innovation require the development of novel technologies to facilitate the sophisticated, multifaceted, high‐paced workflows necessary to support modern large molecule drug discovery. A high‐level aspiration is a true integration of "lab‐on‐a‐chip" methods that vastly miniaturize cellulmical experiments could transform the speed, cost, and success of multiple workstreams in biologics development. Several microscale bioprocess technologies have been established that incrementally address these needs, yet each is inflexibly designed for a very specific process thus limiting an integrated holistic application. A more fully integrated nanoscale approach that incorporates manipulation, culture, analytics, and traceable digital record keeping of thousands of single cells in a relevant nanoenvironment would be a transformative technology capable of keeping pace with today's rapid and complex drug discovery demands. The recent advent of optical manipulation of cells using light‐induced electrokinetics with micro‐ and nanoscale cell culture is poised to revolutionize both fundamental and applied biological research. In this review, we summarize the current state of the art for optical manipulation techniques and discuss emerging biological applications of this technology. In particular, we focus on promising prospects for drug discovery workflows, including antibody discovery, bioassay development, antibody engineering, and cell line development, which are enabled by the automation and industrialization of an integrated optoelectronic single‐cell manipulation and culture platform. Continued development of such platforms will be well positioned to overcome many of the challenges currently associated with fragmented, low‐throughput bioprocess workflows in biopharma and life science research. [ABSTRACT FROM AUTHOR]

In man, the therapeutic effectiveness of specific inhibitors of leukotriene (LT) biosynthesis against allergen-induced bronchoconstriction appears to be related to the in vivo biochemical efficacy of these compounds, as measured by inhibition of whole blood LTB generation (upon A23187 stimulus) and, particularly, urinary LTE excretion. Accordingly, we have assessed the ability of two clinically documented LT biosynthesis inhibitors, zileuton and MK-886, and the structurally novel 5-lipoxygenase activatig protein antagonist, MK-0591, to inhibit the production of these inflammatory arachidonic acid metabolites in laboratory dogs. Zileuton (2 mg/kg) was extremely bioavailable in dogs (>10 μ M plasma concentrations), and inhibited the A23187-induced ex vivo production of LTB by venous blood by >90%, in concordance with its potency in canine blood in vitro (IC=1.1 μ M). Despite this degree of inhibition in whole blood, urinary LTE excretion was reduced by only 52%, a profile of activity similar to that seen in clinical studies. MK-886 was less well absorbed, with plasma concentrations of 3 μ M being achieved only at 25 mg/kg. These levels resulted in <45% inhibition of LTB production, but a significant ( p<0.05) 47% inhibition of urinary LTE excretion. MK-0591 was similarly bioavailable (compared with MK-886), but 10-fold more active in vivo as a 2 mg/kg dose resulted in 41-62% inhibition of urinary LTE excretion ( p<0.05 vs controls; n=4, 28). Significant inhibition of ex vivo LTB synthesis was also observed at this dose (49%), in accord with peak plasma concentrations of 0.5 μ M and an in vitro potency of 0.2-0.4 μ M (IC) in whole blood from these animals. At higher dose (10 mg/kg), MK-0591 inhibited LTE excretion by 69%, with 88% inhibition of the LT biosynthetic capacity of whole blood. These data demonstrate that the biochemical efficacy of structurally diverse leukotriene biosynthesis inhibitors can be assessed in vivo in normal laboratory dogs. Such measurements, combined with bioavailability data from other species, may be useful for predicting biochemical activity in man. [ABSTRACT FROM AUTHOR]

Abstract: Inhibition of the PHD2 enzyme has been associated with increased red blood cell levels. From a screening hit, a series of novel hydroxyl-thiazoles were developed as potent PHD2 inhibitors. [Copyright &y& Elsevier]

Abstract: The discovery and SAR of a novel series of substituted 2,2-bisaryl-bicycloheptane inhibitors of 5-lipoxygenase activating protein (FLAP) are herein described. SAR studies have shown that 2,5-substitution on the exo-aryl group is optimal for potency. The most potent compounds in this series have an ortho-nitrogen aryl linked with a methyleneoxy as the 5-substituent and a polar group such as a urethane as the 2-substituent. One of the most potent compounds identified is the 5-benzothiazolymethoxy-2-pyridinylcarbamate derivative 2 (FLAP IC50 =2.8nM) which blocks 89% of ragweed induced urinary LTE4 production in dogs (at an I.V. dose of 2.5μg/kg/min). This compound inhibits calcium ionophore stimulated LTB4 production in both human polymorphonuclear (PMN) leukocytes and human whole blood (IC50 =2.0 and 33nM, respectively). [Copyright &y& Elsevier]

Abstract: We report the development of the novel N-substituted benzimidazole 11 as a potent and selective human formyl peptide receptor-like 1 (hFPRL1) agonist. This compound and its less active enantiomer 12 were identified as useful tools for studying receptor function in vitro. [Copyright &y& Elsevier]

Abstract: We report the discovery of potent agonists for the human formyl-peptide-like 1 receptor (hFPRL1). These compounds did not act at a closely related receptor denoted human formyl peptide receptor (hFPR) up to 10μM concentration. Recent studies have indicated that agonizing this receptor may promote resolution of inflammation. In an exploratory study, a novel hFPRL1 agonist showed efficacy in a mouse ear inflammation model following oral administration. [Copyright &y& Elsevier]

Abstract: Leukotriene biosynthesis inhibitors have potential as therapeutic agents for asthma and inflammatory diseases. A novel series of substituted coumarin derivatives has been synthesized and the structure–activity relationship was evaluated with respect to their ability to inhibit the formation of leukotrienes via the human 5-lipoxygenase enzyme. [Copyright &y& Elsevier]

A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays. [Copyright &y& Elsevier]