Overview of informatics for high content screening.

With the growing use of high content screening (HCS) and analysis in drug discovery and systems biology, informatics has come to the forefront as a critical technology to effectively utilize the massive volumes of high content data and images being generated. Informatics technologies are required to transform HCS data and images into useful information and then into knowledge to drive decision making in an efficient and cost effective manner. In this chapter, we provide an overview of informatics tools and technologies for HCS, discuss some of the challenges of harnessing the huge and growing volumes of HCS data, and provide insight to help toward implementing or selecting, and utilizing a high content informatics solution to meet your organization's needs.

Synthesis and structure-activity relationship of novel 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones as progesterone receptor modulators leading to the potent and selective nonsteroidal progesterone receptor agonist tanaproget.

Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.

3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides: potent, non-peptidic agonists of both the micro and delta opioid receptors.

Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.

Furan-Terminated N-Acyliminium Ion Initiated Cyclizations in Alkaloid Synthesis.

A study of the utility of furan-terminated N-acyliminium ion initiated cyclizations for the synthesis of linearly fused alkaloid precursors (Figure 2) is presented. The outcome of the cyclization event depends on the position of furan tether attachment (2 vs 3), tether length, and furan 5-substituent (R = H, CH(3), Ar). 3-Substituted furans cyclized to form 6- and 7-membered ring containing furans 35-38, 50, and 51 in good to excellent yields. 2-Substituted furans closed to form only 6-membered rings; however, the products obtained were a function of the furan 5-substituent. The 5-H furans 17 and 18 led exclusively to the corresponding furans 21 and 22, while the 5-CH(3)-furans 42 and 43 gave only diketone containing compounds 44 and 45. 5-Arylfurans 66-71 provided mixtures of furan- and diketone-containing products 72-83, with the ratio related to the substitution on the phenyl moiety. A preparation of epilupinine 10 is also discussed.

Generating 'omic knowledge': the role of informatics in high content screening.

High Content Screening (HCS) and High Content Analysis (HCA) have emerged over the past 10 years as a powerful technology for both drug discovery and systems biology. Founded on the automated, quantitative image analysis of fluorescently labeled cells or engineered cell lines, HCS provides unparalleled levels of multi-parameter data on cellular events and is being widely adopted, with great benefits, in many aspects of life science from gaining a better understanding of disease processes, through better models of toxicity, to generating systems views of cellular processes. This paper looks at the role of informatics and bioinformatics in both enabling and driving HCS to further our understanding of both the genome and the cellome and looks into the future to see where such deep knowledge could take us.

Novel pyrrole-containing progesterone receptor modulators.

A series of 1,4-dihydro-2H-[d][3,1]-benzoxazin-2-one and 1,3-dihydro-[3H]-indol-2-one containing 6- or 5-, respectively, appended substituted pyrrole moieties were synthesized and evaluated for their ability to modulate the activity of the progesterone receptor (PR). Key structural changes to the pyrrole moieties of these molecules were shown to have a predictive influence as to whether the compounds behaved as PR agonists or antagonists. Compounds with the 5(')-cyano-2(')-pyrrole moiety (e.g., 32, 33, and 38) were shown to be potent PR agonists (EC(50)'s of 1.1, 1.8, and 2.8 nM, respectively). Compounds with the 5(')-nitro-2(')-pyrrole moiety (e.g., 34 and 36) were shown to be PR antagonists (IC(50)'s of 180 and 36 nM, respectively).

New progesterone receptor antagonists: 3,3-disubstituted-5-aryloxindoles.

A new series of 3,3-disubstituted-5-aryloxindoles has been synthesized and evaluated for progesterone receptor antagonist (PR) activity in a T47D cell alkaline phosphatase assay and for their ability to bind PR in competition binding studies. In this communication, the synthesis and structure-activity relationships (SARs) of various 3,3-substituents are discussed where it is clear that small alkyl and spiroalkyl groups are required to achieve better PR antagonist activity.