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Trinity College Dublin

Personal Information
College Photo Name Gilmer, John Francis
Main Department Pharmacy
College Title Assistant Professor
E-mail gilmerjf@tcd.ie
College Tel +353 1 896 2795
Web http://people.tcd.ie/gilmerjf
Fax +353 1 896 2793
 
Representations
Details Date
Member, DMMC Cancer Principal Investigators, Trans-institutional grouping of Principal Investigators leading research on Cancer themes
Member, Core Technology PI's, DMMC Principal Investigators leading the development of core technology platforms.
Member, Centre for Research into Global Disease (Proposed), This consortium combines researchers with complementary interests in globally significant infectious disease. Interests include innate immunity, immune regulation, regional immunity, immune evasiob, vaccine & adjuvant development as well as drug & target development.
Invitee, Colorectal & GI Cancer Research Group (Proposed), Speculative idea to cluster PI's around collaborative study on Upper GI and Colon Cancers.Deliberately wide selection of surgeons, pathologists and academic researchers based on stated interest or publication in fields of oesophageal or colorectal cancer.To be reviewed/focused by DK/JR/PMacM.Extracted from DMMC Research Database - 8 Nov 2004.
Member, PHG Funded PI's and Researchers, All Researchers funded under Cycle 3 PRTLI - Programme for Human Genomics
 
Membership of Professional Institutions, Associations, Societies
Details Date From Date To
Member of European Federation of Pharmaceutical Scientists
 
Description of Research Interests
i) Enzyme inhibitors • Isosorbide-based inhibitors of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE): synthesis and biochemistry; the role of BuChE in Alzheimer's disease • Rational design of selective covalent inhibitors of COX-2 • Rational design, synthesis and testing of inhibitors for thyrotropin-releasing hormone-degrading ectoenzyme (TRH-DE) ii) Prodrugs and metabolic hydrolysis • Design and evaluation of aspirin-based antiplatelet agents with reduced gastric toxicity relative to aspirin • Intelligent prodrug carrier systems for targeting corticosteroids to the colon • Exploring metabolic vectors for site specific drug delivery
 
Research Interests
ASPIRIN BINDING BIOLOGICAL-MEMBRANES BUTYRYLCHOLINESTERASE
Design, synthesis and testing of specific enzyme inhibitors ENZYME SUBSTRATE SPECIFICITIES HOST-GUEST CHEMISTRY HYDROLYSIS
IMPROVED DELIVERY Isosorbide-based therapies for Alzheimer's disease MOLECULAR RECOGNITION PRODRUG
Pro-drug design for tissue targeting RECEPTORS STEROIDS Thyrotropin-releasing hormone-degrading ectoenzyme inhibitors in the treatment of CNS disorders
 
Research Projects
Project title Investigation into highly potent inhibitors of butyrylcholinesterase
Summary The central nervous system contains two cholinesterases; acetylcholinesterase [EC 3.1.1.7; AChE] and butyrylcholinesterase [EC 3.1.1.8; BuChE]. These are probably the most widely studied enzymes due to their extraordinary speed and the important relationship between AChE and the neurotransmitter acetylcholine (ACh). Surprisingly, no physiological role has been assigned to BuChE, nor has it a known endogenous substrate (Darvesh et al., 2003). It is difficult to accept that this enzyme has been retained without function in the evolving organism: for the present it takes its name from butyrylcholine, a synthetic substance it hydrolyses exceedingly rapidly. Interest in BuChE has risen sharply due to emerging evidence of its involvement in Alzheimer’s disease (Giacobini, 2003, 2004). We have recently discovered that human BuChE hydrolyses some isosorbide-2-esters at higher rates than butyrylcholine itself (Gilmer et al., 2002, 2005). We hypothesised that this could be used in the design of novel inhibitors of BuChE. Our design involved replacement of the vulnerable ester with carbamate functionality, which is esterase inhibitory. The approach proved highly successful. Many of the compounds in the new class exhibit nanomolar potency. The current lead compound has an IC50 of 150 picoM and more than 65,000-fold selectivity for BuChE over AChE. It is the most potent and BuChE-selective compound ever reported. It is also completely unlike any other BuChE inhibitor or substrate type. Furthermore, it is uncharged at physiological pH and highly lipophilic, attributes generally required for good blood brain barrier penetrability. These compounds hold significant promise in probing the biological role of BuChE and potentially in Alzheimer’s therapy. The aim of this project is to find out how the esters and carbamates interact with both cholinesterases and to begin exploring their therapeutic potential using medicinal chemistry in combination with clinically relevant models of AD. The overall purpose of the program is to examine the hypothesis that BuChE is a rogue protein in AD. Collaborators: Sean Reidy, Sheila Ryder
Funding Agency SFI
Programme Research-Frontiers 2005_CHE046
Type of Project Basic Research
Date from 2005
Date to 2008
Person Months 72


Project title A new system for targeting steroids to the colon
Summary Drug targeting may be defined as the delivery of a drug to a specific organ, tissue or cell population. This field offers the prospect of enhancing the efficacy of drug treatment while reducing systemic impact or side effects. Despite the promise of this approach, and ongoing efforts, there have been few successful examples to date due in part to limited understanding of the basic factors underlying drug transport and the expression of potential targeting vectors. Chemical drug targeting involves the deliberate modification of a structure (usually bioreversibly) causing it to accumulate in a target tissue; site-specific release from the prodrug is triggered by a chemical or enzymatic condition not present elsewhere in the body. The colon is an important challenge to the validity of the drug targeting approach, as conditions in the colon are largely similar to those prevailing elsewhere in the gastrointestinal (GI) system, and the luminal pH gradient through the GI tract is too gradual for effective local drug release on strictly chemical grounds. On the other hand, the colon is an important drug target for the treatment of pathologies of the colon itself, such as inflammatory bowel disease (IBD) and colon cancer, and for the relief of the chronic constipation that accompanies opioid drug treatment. One key difference between the colon and small intestine that might be exploited as a vector for site-specific drug release, is the luxuriant microflora of the former. The GI tract has a steadily increasing bacterial concentration gradient on descending from the stomach through the small intestine, followed by an enormous increase at the colon. These organisms fulfil their energy needs by fermenting undigested materials entering from the small intestine (particularly polysaccharides) and have for this purpose evolved an elaborate array of enzymes such as, azoreductase, glucosidase, -glucuronidase, -xylosidase, nitroreductase, galactosidase and deaminase. This abrupt increase in bacterial enzyme expression has been investigated as a means of targeting drugs to the colon, especially those for the treatment of IBD. One outstandingly successful outcome of these endeavours has been the development of azo-based prodrugs of 5-amino salicylic acid (5-ASA), which because of their hydrophilicity and polarity pass through the GI system intact before releasing their 5-amino salicylic acid ‘payload’ on reduction of the azo linker by azoreducases associated with colonic microflora. Several drugs based on this concept, such as ipsalizide, balsalazide 2, sulphasalazine (the prototype) and olsalazide 3, are in clinical use for the treatment of IBD The targeting of other drug types, such as the anti-inflammatory steroids to the colon has been less successful. Paradoxically, the need for appropriate systems in these cases is more pressing because steroids have multiple systemic side effects when administered orally due to their ready absorption from the stomach and small intestine. Chronic inflammatory bowel disease comprises two major disorders, namely ulcerative colitis and Crohn’s disease. Both of these conditions produce significant morbidity in the form of diarrhoea, weight loss and potentially serious and life-threatening complications. It is therefore unsurprising that intense efforts have been made both to unravel the underlying aetiology of IBD and develop new therapies; but also to improve existing pharmacotherapy, which is mainly restricted to 5-ASA derivatives and steroids. This project is directed at the design of a new type of prodrug carrier for glucorcorticoids that will allow site-specific release in the colon following oral administration. Collaborators: Dermot Kelleher
Funding Agency Enterprise Ireland
Programme Proof of Concept 2005066, Innovations Partnership with OPSONA
Type of Project Applied
Date from 2005
Date to 2009
Person Months 48


Project title Exploiting chemical libraries, structural analysis and biological testing to design thyrotropin-releasing hormone-degrading ectoenzyme (TRH-DE) inhibitors for use in the treatment of CNS disorders
Summary
Funding Agency Health Research Board
Programme Interdisciplinary (Kelly, Gilmer, Tipton and O'Meara)
Type of Project Translational
Date from 2002
Date to 2004
Person Months 24


Project title Development of novel aspirin prodrugs
Summary Regular aspirin use is associated with reduced risk of mortality in all cardiovascular risk groups. This effect is attributed to aspirin’s inhibition of platelet COX-1. In addition, numerous observational studies indicate that aspirin use reduces the risk of colorectal, oesophageal, gastric and lung cancers. Aspirin’s cytoprotective effects have been attributed to its unique ability to acetylate COX-2, which causes arachidonic acid to be shunted away from PGE2, a cancer promoter, towards HETE, a cancer suppressor. There are not yet reliable dose-related data for the prophylactic use of aspirin in cancer; however, it seems likely to be higher than the optimal dose required for its established role in the prevention of heart attack. Other findings suggest a protective role for aspirin in Alzheimer’s disease and other forms of dementia. The main side effect associated with aspirin use is gastric bleeding. Endoscopically controlled studies demonstrate an increased risk of bleeding at all doses (75mg = 2.3, 150 mg =3.2, 300 mg = 3.9): in one recent study 10% of patients on low dose aspirin (10-300 mg/day) had endoscopic ulcers after 12 weeks, with one case occurring at 10 mg/day. Elevated bleeding was observed in several studies 5 to 30 days after the start of therapy indicating that adaptation does not occur. Significantly, the risk of GI side-effects has limited aspirin use to patient groups with a high probability of a thrombotic event. A potentially valuable approach to this problem is the design of aspirin derivatives capable of delaying aspirin-release until after absorption. This would effectively abolish the local component of gastric toxicity, associated with direct contact between the aspirin carboxylic acid and the gastric mucosa. Secondly, prostaglandin levels in the gastric microcirculation should be unaffected during the first pass since aspirin esters do not have intrinsic cyclo-oxygenase inhibitory activity. This project is concerned with a novel design that will permit for the first time the dual release of aspirin and nitric oxide from the same drug molecule.
Funding Agency Enterprise Ireland
Programme EI 2005 0257, EI Tech Dev 2007-2009
Type of Project applied
Date from 2006
Date to 2007
Person Months 72


Project title Isosorbide as a building block for novel human butyrylcholinesterase probes
Summary This project included some preliminary kinetics and modelling approaches to isosorbide-BuChE interactions. Collaborator: Sean Reidy (AIT)
Funding Agency Enterprise Ireland
Programme BRGS 2002 0304
Type of Project Basic
Date from 2002
Date to 2005
Person Months 72


More Research Projects>>>
 
Publications and Other Research Outputs
Peer Reviewed
C. Mills, B. J. Cleary, J. F. Gilmer and J. J. Walsh, Inhibition of acetylcholinesterase by Tea Tree oil, The Journal of pharmacy and pharmacology, 56, (3), 2004, p375-9
URL
J. F. Gilmer, M. A. Murphy, J. A. Shannon, C. G. Breen, S. A. Ryder and J. M. Clancy, Single oral dose study of two isosorbide-based aspirin prodrugs in the dog, The Journal of pharmacy and pharmacology, 55, (10), 2003, p1351-7
URL
P. S. Gardiner and J. F. Gilmer, The medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs, Mini reviews in medicinal chemistry, 3, (5), 2003, p461-70
URL
J. F. Gilmer, L. M. Moriarty, M. N. Lally and J. M. Clancy, Isosorbide-based aspirin prodrugs. II. Hydrolysis kinetics of isosorbide diaspirinate, European journal of pharmaceutical sciences, 16, (04-May), 2002, p297-304
URL
J. F. Gilmer, L. M. Moriarty, D. F. McCafferty and J. M. Clancy, Synthesis, hydrolysis kinetics and anti-platelet effects of isosorbide mononitrate derivatives of aspirin, European journal of pharmaceutical sciences, 14, (3), 2001, p221-7
URL
More Publications and Other Research Outputs >>>
 

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