The phosphoinositide 3‐kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3‐dihydroimidazo[1,2‐c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure–activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80‐6946) as a clinical candidate for the treatment of solid and hematological tumors are described.

A common procedure for studying the effects on cognition of repetitive transcranial magnetic stimulation (rTMS) is to deliver rTMS concurrent with task performance, and to compare task performance on these trials versus on trials without rTMS. Recent evidence that TMS can have effects on neural activity that persist longer than the experimental session itself, however, raise questions about the assumption of the transient nature of rTMS that underlies many concurrent (or "online") rTMS designs. To our knowledge, there have been no studies in the cognitive domain examining whether the application of brief trains of rTMS during specific epochs of a complex task may have effects that spill over into subsequent task epochs, and perhaps into subsequent trials. We looked for possible immediate spill-over and longer-term cumulative effects of rTMS in data from two studies of visual short-term delayed recognition. In 54 subjects, 10-Hz rTMS trains were applied to five different brain regions during the 3-s delay period of a spatial task, and in a second group of 15 subjects, electroencephalography (EEG) was recorded while 10-Hz rTMS was applied to two brain areas during the 3-s delay period of both spatial and object tasks. No evidence for immediate effects was found in the comparison of the memory probe-evoked response on trials that were vs. were not preceded by delay-period rTMS. No evidence for cumulative effects was found in analyses of behavioral performance, and of EEG signal, as a function of task block. The implications of these findings, and their relation to the broader literature on acute vs. long-lasting effects of rTMS, are considered.

In the United States, the dramatic increase in jet fuel usage and kilometers flown has led to speculation of a similar increase in jet contrails. However, contrail occurrence depends heavily upon the meteorological conditions near cruising altitudes (i.e. the tropopause, 10-12 km altitude). This study reports a contrail mid-season contemporary climatology for the coterminous United States (2000-2002), and compares the frequencies with those previously reported for an earlier (1977-1979) period, to determine spatial and seasonal contrail frequency changes. For both climatologies, contrail occurrence is derived from the analysis of high-resolution satellite imagery. Data on US jet aircraft flight activity were obtained to assess their relationship to contrail frequency, as were NCEP-NCAR reanalysis data to determine the changes in tropopause-level atmospheric conditions. For the 2000-2002 period, contrails comprise a distinct high (low) frequency pattern in the East (West) halves of the United States. Seasonally, there is a contrail association with the latitudinal migration of the jet stream and a US-wide peak contrail frequency during winter (January). The inter-monthly variations in contrail frequency are significantly different from each other but show no association with variations in jet flight activity, indicating a greater role for meteorological conditions. Between the 1977-1979 and 2000-2002 periods, there were strong spatial and seasonal asymmetries to the contrail frequency change. These involve a cooling (warming) of the tropopause for the largest (smallest) frequency increases, which shows some association with the switch in positive and negative phases of the Arctic Oscillation. The role of upper tropospheric conditions and links to hemi spheric- scale teleconnections should be considered when projecting contrail frequency changes and their future impacts on climate. Copyright (c) 2006 Royal Meteorological Society.

A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.

Objective: This study analyzed factors associated with injuries to hospitalized victims of nonfatal immersion-related events in Alaska from 1991 through 2000.Data: Alaska Trauma Registry (ATR) records of Victims of nonfatal immersion events requiring hospitalization were examined to identify factors associated with injury outcomes. Subjects were divided into two groups: the "immersion only" (IO) group had no additional injuries associated with their immersion-related events, while subjects in the "associated injury" (AI) group incurred additional trauma during injury events.Results: There were 176 ATR records of nonfatal immersion events. In 87 (49.5%) cases, hospitalizations were due to the effects of immersion only (IO group). In 89 (50.5%) cases, hospitalizations were due not only to the effects of immersion, but also due to additional injuries occurring immediately before or while immersion took place (AI group). The final logistic regression model revealed statistically significant relationships between age greater than 12 years, female gender, white ethnicity, and operation of water transport vehicles, and increased risk for associated injury outcomes (p < 0.05).Discussion: This study is the first of its kind to analyze factors associated with the most severe nonfatal immersion-related injuries in Alaska, and identifies target populations for future safety campaigns. (c) 2005 Elsevier Ltd. All rights reserved.

4,5-Disubstituted cis-pyrrolidinones were investigated as inhibitors of type II 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Early structure-activity relationship patterns for this class of compounds are discussed.

Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.

Heterocyclic ureas, such as N-3-thienyl N'-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure-activity relationships were established, and the potency of the screening hit was improved 10-fold to IC(50)=1.7 microM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC(50)=0.54 microM) for a second generation series of heterocyclic urea raf kinase inhibitors.

Inhibitors of the MAP kinase p38 are potentially useful for the treatment for osteoporosis, arthritis, and other inflammatory diseases. A series of thienyl, furyl, and pyrrolyl ureas has been identified as potent p38 inhibitors, displaying in vitro activity in the nanomolar range.

Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM).

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The MAP kinase p38 has been implicated in cytokine signaling, and its inhibitors are potentially useful for the treatment of arthritis and osteoporosis. Novel small-molecule inhibitors of p38 kinase were derived from a combinatorial chemistry effort and exhibit activity in the nanomolar range. Very steep structure–activity relationships are observed within this class.