Publications by authors named "Rick Morrison"

12 Publications

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Assessing Outsourcing Oversight Practices and Performance.

Ther Innov Regul Sci 2020 01 6;54(1):158-166. Epub 2020 Jan 6.

Tufts Center for the Study of Drug Development (Tufts CSDD), 75 Kneeland Street, Floor 11, Boston, MA, 2741, USA.

Background: The Tufts Center for the Study of Drug Development conducted a study updating benchmarks on outsourcing model adoption and assessing oversight practices and experience.

Methods: An online survey examining organizational use of clinical development outsourcing was distributed between February and April 2018. Responses from a total of 88 individuals were included in the final analysis.

Results: More than half of individuals responding reported using 3 or more models simultaneously, mixing and matching approaches to meet individual project needs. Outsourcing practices among small, medium, and large sponsor companies remain inconsistent and deliver mixed levels of satisfaction and performance. Full-service models are the most commonly used. Biopharmaceutical companies report that the primary purpose of their oversight mechanisms is to minimize risks and regulatory missteps. Oversight mechanisms are generally supported by middle management personnel focusing on more reactive and tactical issues. Executive-level involvement in outsourcing oversight is minimal and highly variable.

Conclusion: Several opportunities to improve oversight practices were identified in the study, including increasing executive-level involvement and leveraging technologies to monitor performance, enhance communication, and expand collaboration capabilities.
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http://dx.doi.org/10.1007/s43441-019-00040-2DOI Listing
January 2020

Synthesis and biological evaluation of 8-aryl-2-morpholino-7-O-substituted benzo[e][1,3]oxazin-4-ones against DNA-PK, PI3K, PDE3A enzymes and platelet aggregation.

Bioorg Med Chem 2017 10 15;25(20):5531-5536. Epub 2017 Aug 15.

Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199 Bendigo, VIC 3552, Australia. Electronic address:

A series of 40 7-(O-substituted)-2-morpholino-8-aryl-4H-benzo[e][1,3]oxazin-4-one derivatives was synthesized. They were prepared via synthesis of a key precursor, 8-bromo-7-hydroxy-2-morpholino-4H-benzo[e][1,3]oxazin-4-one 13 which was amenable to ether synthesis at the 7-position and Suzuki coupling at the 8-position. The 2 protons of 7-OCH in compounds 18g, 18h, 18i, 18l and 18m prove to be magnetically non-equivalent, atropisomerism (axial chirality), as result of sterically hindered rotation of the bulky 8-aryl-substituent. The products were evaluated for their activities against PI3K isoforms, DNA-PK and PDE3. The results showed that this substitution pattern has a deleterious effect on PI3K activities, which may arise from steric hindrance in the active site. PI3Kδ was somewhat more tolerant of this substitution particularly where 8-(4-methoxylphenyl) substituents were present (ICs∼2-3μM). Good activities against PDE3 were also obtained for compounds, with particular members of the 7-(2-pyridinyl) methoxy series 19 showing good inhibition (ICs∼2-3μM), comparable to previously described analogues. A piperazinyl derivative 26a effectively inhibited ADP-induced platelet aggregation with an IC of 8μM.
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http://dx.doi.org/10.1016/j.bmc.2017.08.022DOI Listing
October 2017

Synthesis of linear and angular aryl-morpholino-naphth-oxazines, their DNA-PK, PI3K, PDE3A and antiplatelet activity.

Bioorg Med Chem Lett 2016 11 5;26(22):5534-5538. Epub 2016 Oct 5.

Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, PO Box 199, Bendigo, VIC 3552, Australia. Electronic address:

To continue our study of 2-morpholino-benzoxazine based compounds, which show useful activity against PI3K family enzymes or antiplatelet activity, we designed and synthesized a series of linear 6.7-fused, 5,6-angular fused and 7,8-angular fused-aryl-morpholino-naphth-oxazines. The compounds were prepared from substituted 2-hydroxynaphthoic acid to give the corresponding thioxo analogues 8, 9, 15 and 19. The thioxo products were then converted to the morpholino substituted analogue. The aryl group was introduced by Suzuki coupling of bromo precursors. The products were evaluated for activity at PI3K family enzymes and as platelet aggregation inhibitors and compared to reported unsubstituted analogues. The linear 6.7-fused product 13a and 13b were moderated potent but selective PI3Kδ isoform inhibitors (IC=7.7 and 5.61μM). Good antiplatelet activity was noticed for the angular 7,8-fused compounds 22a, b, k and l with IC=3.0,14.0, 2.0 and 5.0μM respectively. The antiplatelet activity is independent of PDE3.
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http://dx.doi.org/10.1016/j.bmcl.2016.10.003DOI Listing
November 2016

Synthesis, structure elucidation, DNA-PK, PI3K, anti-platelet and anti-bacteria activity of linear 5, 6, and 10-substituted-2-morpholino-chromen-oxazine-dione and angular 3, 4, 6-substituted-8-morpholino-chromen-oxazine-2,10-dione.

J Enzyme Inhib Med Chem 2016 2;31(sup2):86-95. Epub 2016 Jun 2.

a Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University , Bendigo , VIC , Australia.

Coumarin, a naturally occurring or synthesised phytochemical, displays a wide range of biological activities. However, chromen-2-ones fused with 1,3-benzoxazine rings is not well documented and there is a gap in the literature which required engaging. The substituted-2-thioxo-chromen-oxazine linear compounds 14a-i and angular compounds 16a-e were synthesised from the reaction of hydroxy-substituted-chromene-carboxylic 10-13 with freshly prepared PhP(SCN). 2-Morpholino-substituted-chromen-oxazine-4,8-dione and 8-morpholino-substituted-chromen-oxazine-2,10-dione 15a-f and 17 were synthesised from the reaction of the corresponding oxazines 14 and 16 with morpholine. PI3K activity was observed for the hydroxy-substituted-chromene-carboxylic acid of which compound 13b showed moderate PI3Kγ (IC=5.56 μM) and PI3Kα (IC=14.7 μM) activity. Additionally, 8-morpholino-chromen-oxazine-2,10-dione 17a showed isoform selective PI3Kδ activity with IC=5.08 μM with non-DNA-PK ≥ 100 μM. Consequently compound 17a can be considered as a selective PI3Kδ inhibitor with non-DNA-PK at compound concentrations ≥100 μM.
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http://dx.doi.org/10.1080/14756366.2016.1190710DOI Listing
February 2017

Synthesis, structure elucidation, DNA-PK and PI3K and anti-cancer activity of 8- and 6-aryl-substituted-1-3-benzoxazines.

Eur J Med Chem 2016 Mar 27;110:326-39. Epub 2016 Jan 27.

Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia. Electronic address:

The synthesis of 6-aryl, 8- aryl, and 8-aryl-6-chloro-2-morpholino-1,3-benzoxazines with potent activity against PI3K and DNA-PK is described. Synthesis of thirty one analogues was facilitated by an improved synthesis of 3-bromo-2-hydroxybenzoic acid 13 by de-sulphonation of 3-bromo-2-hydroxy-5-sulfobenzoic acid 12 en route to 2-methylthio-substituted-benzoxazine intermediates 17-19. From this series, compound 20k (LTURM34) (dibenzo[b,d]thiophen-4-yl) (IC50 = 0.034 μM) was identified as a specific DNA-PK inhibitor, 170 fold more selective for DNA-PK activity compared to PI3K activity. Other compounds of the series show markedly altered selectivity for various PI3K isoforms including compound 20i (8-(naphthalen-1-yl) a potent and quite selective PI3Kδ inhibitor (IC50 = 0.64 μM). Finally, nine compounds were evaluated and showed antiproliferative activity against an NCI panel of cancer cell lines. Compound 20i (8-(naphthalen-1-yl) showed strong anti-proliferative activity against A498 renal cancer cells that warrants further investigation.
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http://dx.doi.org/10.1016/j.ejmech.2016.01.042DOI Listing
March 2016

Image processing for cameras with fiber bundle image relay.

Appl Opt 2015 Feb;54(5):1124-37

Some high-performance imaging systems generate a curved focal surface and so are incompatible with focal plane arrays fabricated by conventional silicon processing. One example is a monocentric lens, which forms a wide field-of-view high-resolution spherical image with a radius equal to the focal length. Optical fiber bundles have been used to couple between this focal surface and planar image sensors. However, such fiber-coupled imaging systems suffer from artifacts due to image sampling and incoherent light transfer by the fiber bundle as well as resampling by the focal plane, resulting in a fixed obscuration pattern. Here, we describe digital image processing techniques to improve image quality in a compact 126° field-of-view, 30 megapixel panoramic imager, where a 12 mm focal length F/1.35 lens made of concentric glass surfaces forms a spherical image surface, which is fiber-coupled to six discrete CMOS focal planes. We characterize the locally space-variant system impulse response at various stages: monocentric lens image formation onto the 2.5 μm pitch fiber bundle, image transfer by the fiber bundle, and sensing by a 1.75 μm pitch backside illuminated color focal plane. We demonstrate methods to mitigate moiré artifacts and local obscuration, correct for sphere to plane mapping distortion and vignetting, and stitch together the image data from discrete sensors into a single panorama. We compare processed images from the prototype to those taken with a 10× larger commercial camera with comparable field-of-view and light collection.
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http://dx.doi.org/10.1364/AO.54.001124DOI Listing
February 2015

Panoramic monocentric imaging using fiber-coupled focal planes.

Opt Express 2014 Dec;22(26):31708-21

Monocentric lenses provide high-resolution wide field of view imaging onto a hemispherical image surface, which can be coupled to conventional focal planes using fiber-bundle image transfer. We show the design and characterization of a 2-glass concentric F/1.0 lens, and describe integration of 5 Mpixel 1.75µm pitch back-side illuminated color CMOS sensors with 2.5µm pitch fiber bundles, then show the fiber-coupled lens compares favorably in both resolution and light collection to a 10x larger conventional F/4 wide angle photographic lens. We describe assembly of the monocentric lens and 6 adjacent sensors with focus optomechanics into an extremely compact 30Mpixel panoramic imager with a 126° "letterbox" format field of view.
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http://dx.doi.org/10.1364/OE.22.031708DOI Listing
December 2014

Ultrathin four-reflection imager.

Appl Opt 2009 Jan;48(2):343-54

Department of Electrical and Computer Engineering, University of California, San Diego, La Jolla, California 92093, USA.

We present the design and experimental demonstration of an ultrathin four-reflection imager. The F/1.15 prototype imager achieves a focal length of 18.6 mm in a track length of just 5.5 mm, providing a 17 degrees field of view over 1.92 megapixels of a color image sensor with 3 microm pixels. We also present the design and experimental results of pupil-phase encoding and postprocessing, which were applied to extend the depth of field and compensate a small amount of axial chromatic aberration present in the four-reflection imager prototype.
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http://dx.doi.org/10.1364/ao.48.000343DOI Listing
January 2009

Relaxing the alignment and fabrication tolerances of thin annular folded imaging systems using wavefront coding.

Appl Opt 2007 Sep;46(27):6751-8

Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, California 92093, USA.

Annular folded imagers can be up to 10x thinner than corresponding full-aperture imagers, but have tight fabrication tolerances and relatively shallow depth of focus. Wavefront coding, the use of specialized optics with postdetection signal processing, has been used to improve the depth of focus in full-aperture imaging systems. Here we explore the application of wavefront coding to annular folded optics. We compare the design and experimental results for an imaging system with a 38 mm focal length and just 5 mm total track.
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http://dx.doi.org/10.1364/ao.46.006751DOI Listing
September 2007

Ultrathin cameras using annular folded optics.

Appl Opt 2007 Feb;46(4):463-71

Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, CA 92093, USA.

We present a reflective multiple-fold approach to visible imaging for high-resolution, large aperture cameras of significantly reduced thickness. This approach allows for reduced bulk and weight compared with large high-quality camera systems and improved resolution and light collection compared with miniature conventional cameras. An analysis of the properties of multiple-fold imagers is presented along with the design, fabrication, and testing of an eightfold prototype camera. This demonstration camera has a 35 mm effective focal length, 0.7 NA, and 27 mm effective aperture folded into a 5 mm total thickness.
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http://dx.doi.org/10.1364/ao.46.000463DOI Listing
February 2007

Multiaperture imaging.

Appl Opt 2006 May;45(13):2871-83

Department of Electrical and Computer Engineering, University of Arizona, Tuscon 85719, USA.

We study the reconstruction of a high-resolution image from multiple low-resolution images by using a nonlinear iterative backprojection algorithm. We exploit diversities in the imaging channels, namely, the number of imagers, magnification, position, rotation, and fill factor, to undo the degradation caused by the optical blur, pixel blur, and additive noise. We quantify the improvements gained by these diversities in the reconstruction process and discuss the trade-off among system parameters. As an example, for a system in which the pixel size is matched to the diffraction-limited optical blur size at a moderate detector noise level, we can reduce the reconstruction root-mean-square error by 570% by using 16 cameras and a large amount of diversity. The algorithm was implemented on a 56 camera array specifically constructed to demonstrate the resolution-enhancement capabilities. Practical issues associated with building and operating this device are presented and analyzed.
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http://dx.doi.org/10.1364/ao.45.002871DOI Listing
May 2006

Prediction of the oral absorption of low-permeability drugs using small intestine-like 2/4/A1 cell monolayers.

Pharm Res 2003 Mar;20(3):397-405

Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden.

Purpose: To characterize the paracellular route of 2/4/A1 monolayers and to compare the permeabilities of incompletely absorbed oral drugs in 2/4/A1 with those in Caco-2 monolayers.

Methods: The cells were cultivated on permeable supports. The 2/4/ A1 expression of genes associated with tight junctions was compared with that in the small intestine using RT-PCR. The aqueous pore radii were determined using paracellular marker molecules. The permeabilities of a series of incompletely absorbed drugs (defined as having a fraction absorbed 0 to 80%) after oral administration to humans were studied.

Results: Occludin and claudin 1 and 3 were expressed in 2/4/A1. The pore radius of 2/4/A1 was 9.0 +/- 0.2 A. which is similar to that in the human small intestine, although the pore radius was smaller (3.7 +/- 0.1 A) in Caco-2. The relationship between permeability and fraction absorbed of 13 drugs was stronger in 2/4/A1 than in Caco-2. The relationships were used to predict the intestinal absorption of another seven drugs. The prediction was more accurate in 2/4/A1 (RMSE = 15.6%) than in Caco-2 (RMSE = 21.1%). Further, Spearman's rank coefficient between FA and permeability was higher in 2/4/A1.

Conclusion: The improved 2/4/A1 cell culture model has a more in vivo-like permeability and predicted the oral absorption of incompletely absorbed drugs better than Caco-2 cells.
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http://dx.doi.org/10.1023/a:1022699920043DOI Listing
March 2003
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