Andrew Griffin
AstraZeneca
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Publication
Featured researches published by Andrew Griffin.
Bioorganic & Medicinal Chemistry Letters | 2011
Tim Luker; Lilian Alcaraz; Kamaldeep K. Chohan; Niklas Blomberg; Dearg S. Brown; Roger John Butlin; Thomas Elebring; Andrew Griffin; Simon D. Guile; Stephen St-Gallay; Britt-Marie Swahn; Steve Swallow; Michael J. Waring; Mark C. Wenlock; Paul D. Leeson
A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.
Journal of Medicinal Chemistry | 2014
Dean G. Brown; Peter R. Bernstein; Andrew Griffin; Steve Wesolowski; Denis Labrecque; Maxime C. Tremblay; Mark Sylvester; Russell C. Mauger; Phillip D. Edwards; Scott Throner; James Folmer; Joseph Cacciola; Clay W Scott; Lois Ann Lazor; Mehrnaz Pourashraf; V. Santhakumar; William Potts; Simon Sydserff; Pascall Giguère; Carine Lévesque; Mohammed Dasser; Thierry Groblewski
A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.
Bioorganic & Medicinal Chemistry Letters | 2009
Paul Jones; Andrew Griffin; Lars Gawell; Rico Lavoie; Daniel Delorme; Edward Roberts; William Brown; Christopher Walpole; Wenhau Xiao; Jamie Boulet; Maryse Labarre; Martin Coupal; Joanne Butterworth; Stephane St-Onge; Lejla Hodzic; Dominic Salois
We have investigated a series of phenolic diaryl amino piperidine delta opioid receptor agonists, establishing the importance of the phenol functional group and substitution on the piperdine nitrogen for delta agonist activity and selectivity versus the mu and kappa opioid receptors. This study uncovered compounds with improved agonist potency and selectivity compared to the standard, non-peptidic delta agonist SNC-80. In vivo anti-nociceptive activity of analog 8e in two rodent models is discussed, demonstrating the potential of delta agonists to provide a novel mechanism for pain relief.
Journal of Biomolecular Screening | 2013
Stephen Zicha; Olivier Radresa; Patricia Laplante; Michael J. Morton; Karen Jones; Martin Main; Shephali Trivedi; Ron P. Julien; Andrew Griffin; Jean Labrecque; Sultan Ahmad; William Brown
TRPV1 was originally characterized as an integrator of various noxious stimuli such as capsaicin, heat, and protons. TRPV1-null mice exhibit a deficiency in sensing noxious heat stimuli, suggesting that TRPV1 is one of the main heat sensors on nociceptive primary afferent neurons and a candidate target for heat hypersensitivity in chronic pain. Several different potent and selective TRPV1 antagonists have been developed by more than 50 companies since the characterization of the receptor in 1997. A consequence of this competitive interest is the crowding of patentable chemical space, because very similar in vitro screening assays are used. To circumvent this issue and to expand our understanding of TRPV1 biology, we sought to take advantage of recent advancements in automated patch-clamp technology to design a novel screening cascade. This SAR-driving assay identified novel modulators that blocked the depolarization-induced activation of outwardly-rectifying TRPV1 currents independent of agonist stimulation, and we correlated the pharmacology to three other innovative assays for higher-throughput screening. Ultimately, we have identified a screening paradigm that would have good predictive value for future TRPV1 drug discovery projects and novel chemical space with a higher probability of gaining intellectual property coverage.
Bioorganic & Medicinal Chemistry Letters | 2012
Yevgeni Besidski; William Brown; Johan Bylund; Michael Dabrowski; Sophie Dautrey; Magali Harter; Lucy Horoszok; Yin Hu; Dean Johnson; Shawn Johnstone; Paul Jones; Sandrine Leclerc; Karin Kolmodin; Inger Kers; Maryse Labarre; Denis Labrecque; Jennifer M.A. Laird; Therese Lundström; John Martino; Mickaël Maudet; Alexander Munro; Martin Nylöf; Andrea Penwell; Didier Rotticci; Andis Slaitas; Anna K. Sundgren-Andersson; Mats Svensson; Gitte Terp; Huascar Villanueva; Christopher Walpole
Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.
Bioorganic & Medicinal Chemistry Letters | 2009
Andrew Griffin; William Brown; Christopher Walpole; Martin Coupal; Lynda Adam; Mylène Gosselin; Dominic Salois; Pierre-Emmanuel Morin; Marie Roumi
We have investigated phenol replacements in a series of diaryl amino piperidine delta opioid agonists. From this study we have demonstrated that the hydroxy functional group can be replaced with a primary amide group, giving enhanced activity at the delta receptor, increased selectivity versus mu and kappa as well as improved in vitro metabolic stability.
Archive | 2003
William Brown; Andrew Griffin; Paul Jones; Daniel Page; Niklas Plobeck; Christopher Walpole
Archive | 2004
William Brown; Andrew Griffin; Thomas AstraZeneca Wilmington Hudzik; Carla AstraZeneca Wilmington Maciag; Gennady AstraZeneca Wilmington Smagin; Christopher Walpole
Archive | 2008
James Arnold; Todd Andrew Brugel; Scott Throner; Steven Wesolowski; Phil Edwards; Andrew Griffin; Thierry Groblewski; Denis Labrecque
Archive | 2008
James Arnold; Todd Andrew Brugel; Scott Throner; Steven Wesolowski; Phil Edwards; Andrew Griffin; Thierry Groblewski; Denis Labrecque