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John Gilmer
Professor in Pharmaceutical Chemistry, Pharmacy

Publications and Further Research Outputs

Peer-Reviewed Publications

Gavin J, Quilty F, Majer F, Gilsenan G, Byrne A.M, Long A, Radics G, Gilmer J.F, A fluorescent analogue of tauroursodeoxycholic acid reduces ER stress and is cytoprotective, Bioorganic and Medicinal Chemistry Letters, 26, (21), 2016, p5369 - 5372 Journal Article, 2016 URL DOI

Jones M, Wang J, Harmon S, Kling B, Heilmann J, Gilmer J.F, Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer's Disease, Molecules, 21, (4), 2016, p440- Journal Article, 2016 DOI URL TARA - Full Text

Glezeva N, Gilmer J.F, Watson C.J, Ledwidge M, A Central Role for Monocyte-Platelet Interactions in Heart Failure, Journal of Cardiovascular Pharmacology and Therapeutics, 21, (3), 2015, p245 - 261 Journal Article, 2015 URL TARA - Full Text DOI

O'Sullivan S, Gilmer JF, Medina C, Matrix metalloproteinases in inflammatory bowel disease: an update, Mediators of Inflammation, 2015, p964131- Review Article, 2015 DOI TARA - Full Text

Santos-Martinez, M.J., Tomaszewski, K., Medina, C., Bazou, D., Gilmer, J.F., Radomski, M.W. , Pharmacological characterization of nanoparticle-induced platelet microaggregation using quartz crystal microbalance with dissipation: comparison with light aggregometry, International Journal of Nanomedicine, 10, 2015, p5107 - 5119 Journal Article, 2015 TARA - Full Text DOI

Bermingham M, Shanahan MK, O'Connell E, Dawkins I, Miwa S, O'Hanlon R, Gilmer J, McDonald K, Ledwidge M., Aspirin Use In Heart Failure: Is Low Dose Therapy Associated With Mortality And Morbidity Benefits In A Large Community Population?, Circulation: Heart Failure, 7, (2), 2014, p243-250 Journal Article, 2014 DOI

N Glezeva, M Santos-Martinez, C Watson, K Mcdonald, C Medina, J Gilmer, M Ledwidge, Inhibition of thromboxane pathways in monocytes impedes cell invasiveness, European Journal of Heart Failure, 16, 2014, pp208-209 Conference Paper, 2014

Shane O'Sullivan; Carlos Medina; Mark Ledwige; Marek W Radomski; John F Gilmer, Nitric oxide-matrix metaloproteinase-9 interactions: Biological and pharmacological significance NO and MMP-9 interactions, Biochimica et Biophysica Acta - Molecular Cell Research, 1843, (3), 2014, p603-617 Journal Article, 2014 DOI

O'Byrne,Paul Matthew P.M., Williams,Robert P. R.P., Walsh,John J. J.J., Gilmer,John F. J.F., Synthesis, screening and pharmacokinetic evaluation of potential prodrugs of bupropion. part one: In vitro development, Pharmaceuticals, 7, (5), 2014, p595-620 Journal Article, 2014 DOI

O'Byrne,Paul Matthew P.M., Williams,Robert P. R.P., Walsh,John J. J.J., Gilmer,John F. J.F., Part two: Evaluation of N-methylbupropion as a potential bupropion prodrug, Pharmaceuticals, 7, (6), 2014, p676-694 Journal Article, 2014 DOI

Radziwon-Balicka A, Santos-Martinez MJ, Corbalan JJ, O'Sullivan S, Treumann A, Gilmer JF, Radomski MW, Medina C., Mechanisms of platelet-stimulated colon cancer invasion: Role of clusterin and thrombospondin 1 in regulation of the P38MAPK-MMP-9 pathway, Carcinogenesis, 35, (2), 2014, p324-332 Journal Article, 2014 DOI

V Voon, C Watson, N Glezeva, M Bermingham, J Wang, R O'Hanlon, J Baugh, K Mc Donald, J Gilmer, M Ledwidge, Doxycycline attenuates matrix metalloproteinase release from inflammatory cells in-vitro and in patients with asymptomatic left ventricular diastolic dysfunction, EUROPEAN JOURNAL OF HEART FAILURE, 16, 2014, pp91- Conference Paper, 2014

Marquez Ruiz JF, Kedziora K, O'Reilly M, Maguire J, Keogh B, Windle H, Kelleher DP, Gilmer JF., Azo-reductase activated budesodine prodrugs for colon targeting., Bioorganic and Medicinal Chemistry Letters, 22, (24), 2013, p573-7 Journal Article, 2013 DOI

Rogers, L.; Majer, F.; Sergeeva, N. N.; Paszko, E.; Gilmer, J. F.; Senge, M. O., Synthesis and biological evaluation of Foscan® bile acid conjugates to target esophageal cancer cells, Bioorganic & Medicinal Chemistry Letters, 23, (9), 2013, p2495-2499. Journal Article, 2013 TARA - Full Text DOI

Ferenc Májer, Ruchika Sharma, Claire Mullins, Luke Keogh, Sinead Phipps, Shane Duggan, Dermot Kelleher, Stephen Keely, Aideen Long, Gábor Radics, Jun Wang, John F. Gilmer, New highly toxic bile acids derived from deoxycholic acid, chenodeoxycholic acid and lithocholic acid, Bioorganic Medicinal Chemistry, 22, (1), 2013, p256-268 Journal Article, 2013 DOI

Simplício AL, Coroadinha AS, Gilmer JF, Lamego J., A methodology for detection and quantification of esterase activity., Methods in Molecular Biology, 984, 2013, p309-19 Journal Article, 2013 DOI

Gavin J, Ruiz JF, Kedziora K, Windle H, Kelleher DP, Gilmer JF., Structure requirements for anaerobe processing of azo compounds: implications for prodrug design., Bioorganic and Medicinal Chemistry Letters, 22, (24), 2013, p7647-7652 Journal Article, 2013 DOI

Kelly OB, Mroz MS, Ward JB, Colliva C, Scharl M, Pellicciari R, Gilmer JF, Fallon PG, Hofmann AF, Roda A, Murray FE, Keely SJ., Ursodeoxycholic acid attenuates colonic epithelial secretory function., Journal of Physiology, 2013, p2307-2318 Journal Article, 2013 DOI TARA - Full Text

Marquez Ruiz JF, Kedziora K, Pigott M, Keogh B, Windle H, Gavin J, Kelleher DP, Gilmer JF., A nitrophenyl-based prodrug type for colorectal targeting of prednisolone, budesonide and celecoxib., Bioorg Med Chem Lett, 23, (6), 2013, p1693-8 Journal Article, 2013 DOI

Wang J, Radomski MW, Medina C, Gilmer JF., MMP inhibition by barbiturate homodimers., Bioorganic and Medicinal Chemistry Letters, 23, (2), 2013, p444-7 Journal Article, 2013 DOI

Jolanta Majka, Rafal Pabianczyk, Gracjana Krzysiek-Maczka, Agata Ptak-Belowska, Slawomir Kwiecien, Anne-Marie Byrne, Dermot P Kelleher, John Gilmer, Tomasz Brzozowski, Mo1930 Beneficial Effect of Ursodeoxycholic Acid (UDCA) and Its Derivative UDCA-Cpa in Attenuation of Functional Impairment of Esophageal Mucosa in Rat Model of Barrett's Esophagus, Gastronenterology, 144, (5), Saunders, 2013, ppS-697-S-698 Meeting Abstract, 2013

Luke Rogers; Ferenc Majer; Natalia N Sergeeva; Edyta Paszko; John F Gilmer, Senge Mathias, Synthesis of Foscan® Bile Acid Conjugates for Use in Photodynamic Therapy , Bioorganic and Medicinal Chemistry Letters, 23, (9), 2013, p2495-2499 Journal Article, 2013 DOI

F Quilty, F Majer, A Long, J Gilmer, THE USE OF FLUORESCENT BILE ACIDS TO CHARACTERISE UPTAKE IN OESOPHAGEAL CELLS, Gut, 2013, 62, Suppl 2, BMJ Publishing Group Ltd and British Society of Gastroenterology, 2013, ppA1 Meeting Abstract, 2013

Medina C, Harmon S, Inkielewicz I, Santos-Martinez MJ, Jones M, Cantwell P, Bazou D, Ledwidge M, Radomski MW, Gilmer JF., Differential inhibition of tumour cell-induced platelet aggregation by the nicotinate aspirin prodrug (ST0702) and aspirin, British Journal of Pharmacology, 166, (3), 2012, p938-949 Journal Article, 2012 DOI

Harmon S, Inkielewicz-Stepniak I, Jones M, Ledwidge M, Santos-Martinez MJ, Medina C, Radomski MW, Gilmer JF., Mechanisms of aggregation inhibition by aspirin and nitrate-aspirin prodrugs in human platelets., Journal of Pharmacy and Pharmacology, 64, (1), 2012, p77-89 Journal Article, 2012 TARA - Full Text DOI

Wang, J., O'Sullivan, S., Harmon, S., Keaveney, R., Radomski, M., Medina, C., Gilmer, J. , Design of barbiturate-nitrate hybrids that inhibit MMP-9 and secretion, Journal of Medicinal Chemistry, 55, 2012, p2154 - 2162 Journal Article, 2012 DOI

Mark T. Ledwidge, Fiona Ryan, David M Kerins, Damian O'Connell, Gene Cafali, Shona Harmon, Michael Jones, John F Gilmer, In-vivo impact of prodrug isosorbide-5-nicotinate-2-aspirinate on lipids and prostaglandin D2: is this a new immediate-release therapeutic option for niacin?, Atherosclerosis, 2012 Journal Article, 2012 TARA - Full Text

Ledwidge,Mark Thomas M.T., Ryan,Fiona Siobhan F.S., Kerins,David M. D.M., O'Connell,Damian P. D.P., Cefali,Gene G., Harmon,Shona S., Jones,Michael B. M.B., Gilmer,John F. J.F., In vivo impact of prodrug isosorbide-5-nicotinate-2-aspirinate on lipids and prostaglandin D 2: Is this a new immediate-release therapeutic option for niacin?, Atherosclerosis, 221, (2), 2012, p478-483 Journal Article, 2012 DOI

F Májer, JJ Salomon, R Sharma, SV Etzbach, MNM Najib, R Keaveny, A Long, J Wang, C Ehrhardt, JF Gilmer, New fluorescent bile acids: Synthesis, chemical characterization, and disastereoselective uptake by Caco-2 cells of 3-deoxy 3-NBD-amino deoxycholic and ursodeoxycholic acid, Bioorg Med Chem, 20, (5), 2012, p1767-1778 Journal Article, 2012 TARA - Full Text DOI

D Prichard, R Sharma, A Byrne, DP Kelleher, JF Gilmer, A Long, URSODEOXYCHOLIC ACID MODULATES THE GLUCOCORTICOID RECEPTOR IN OESOPHAGEAL CELLS, Gut, 59, (A119-A119), 2012 Meeting Abstract, 2012

Juan F. Marquez Ruiz, Kinga Kedziora, Henry Windle, Dermot P. Kelleher, John F. Gilmer, Investigation into drug release from colon specific azoreductase activated steroid prodrugs using in vitro models, Journal of Pharmacy and Pharmacology, 63, (6), 2011, p806 - 816 Journal Article, 2011

Sharma R, Long A, Gilmer JF, Advances in bile acid medicinal chemistry., Current medicinal chemistry, 18, (26), 2011, p4029-52 Journal Article, 2011

Sharma R, Prichard D, Majer F, Byrne AM, Kelleher D, Long A, Gilmer JF, Ursodeoxycholic acid amides as novel glucocorticoid receptor modulators., Journal of medicinal chemistry, 54, (1), 2011, p122-130 Journal Article, 2011 DOI

Ruiz JF, Kedziora K, Keogh B, Maguire J, Reilly M, Windle H, Kelleher DP, Gilmer JF, A double prodrug system for colon targeting of benzenesulfonamide COX-2 inhibitors., Bioorganic & medicinal chemistry letters, 21, (22), 2011, p6636-40 Journal Article, 2011 DOI

Ruiz JF, Kedziora K, Windle H, Kelleher DP, Gilmer JF, Investigation into drug release from colon-specific azoreductase-activated steroid prodrugs using in-vitro models., The Journal of pharmacy and pharmacology, 63, (6), 2011, p806-816 Journal Article, 2011 DOI

Marquez Ruiz JF, Kedziora K, Keogh B, Maguire J, Reilly M, Windle HJ, Kelleher D, Gilmer JF, A double prodrug system for colon targeting of benzenesulfonamide COX-2 inhibitors, Bioorganic & Medicinal Chemistry Letters, 21, (22), 2011, p6636-6640 Journal Article, 2011 TARA - Full Text

J Wang, C Medina, MW Radomski, JF Gilmer, N-subsituted homopiperazine barbiturates as gelatinase inhibitors, Bioorganic & Medicinal Chemistry, 19, (16), 2011, p4985-4999 Journal Article, 2011 TARA - Full Text

I Inkielewicz-Stepniak, J Gilmer, M Radomski, W Czarnowski, C Medina, The effect of new aspirin prodrugs on blood platelet and tumor cells in an 'in vitro'study, Toxicology Letters, XII International Congress of Toxicology, Barcelona, 196, 2010, ppS258-S259 Conference Paper, 2010

2. Ledwidge, Mark T.; Ryan, Fiona; Harmon, Shona; Radomski, Marek; Gilmer, John, SUPERASPIRINS: NOVEL PRO-DRUGS ARE MORE EFFECTIVE THAN CONVENTIONAL ASPIRIN AND DO NOT CAUSE DIRECT GI TOXICITY., Journal of the American College of Cardiology, 57, (14), 2010, ppPages:E1908-Na Conference Paper, 2010

9. Sharma R, Kelleher D, Long A, Gilmer JF , SAR of bile acid effects on the Golgi apparatus, Digestive Diseases Weekly, San Diego, 2010 Meeting Abstract, 2010

Sharma, Ruchika; Prichard, David; Majer, Ferenc; Byrne, Annemarie; Kelleher, Dermot; Long, Aideen; Gilmer, John, Ursodeoxycholic acid amides as novel glucocorticoid receptor modulators, Journal of Medicinal Chemistry, jm-2010-00860s.R2, 2010 Journal Article, 2010

Carolan CG, Dillon GP, Khan D, Ryder SA, Gaynor JM, Reidy S, Marquez JF, Jones M, Holland V, Gilmer JF., Isosorbide-2-benzyl carbamate-5-salicylate, a peripheral anionic site binding subnanomolar selective butyrylcholinesterase inhibitor., Journal of Medicinal Chemistry, 53, (3), 2010, p1190 - 1199 Journal Article, 2010

O'Byrne PM, Williams R, Walsh JJ, Gilmer JF., The aqueous stability of bupropion, Journal of Pharmaceutical and Biomedical Analysis, 53, (3), 2010, p376 - 381 Journal Article, 2010 URL

1. Mark T. Ledwidge, Fiona Ryan, Ken McDonald, Mike Jones, Shona Harmon, Ray Keaveny, Marek Radomski, John Gilmer, NOVEL DUAL NITRIC OXIDE RELEASING ANTI-REMODELING THERAPY FOR HYPERTENSIVE HEART DISEASE, ournal of The American College of Cardiology , , 57, (14), 2010, pp. E609-E Meeting Abstract, 2010

Ruchika Sharma, Ferenc Majer, Vijaya Kumar Peta, Jun Wang, Ray Keaveney, Dermot Kelleher, Aideen Long and John F. Gilmer, Bile acid toxicity structure activity relationships: Correlations between cell viability and lipophilicity in a panel of new and known bile acids using an esophageal cell line (HET-1A), Bioorganic & Medicinal Chemistry, 18, (18), 2010, p6886-6895 Journal Article, 2010 TARA - Full Text

Dillon GP, Gaynor JM, Khan D, Carolan CG, Ryder SA, Marquez JF, Reidy S, Gilmer JF., Isosorbide-based cholinesterase inhibitors; replacement of 5-ester groups leading to increased stability., Bioorganic Medicinal Chemistry, 18, (3), 2010, p1045-1053 Journal Article, 2010

Ruchika Sharma, Annemarie Byrne, Aideen Long, Dermot Kelleher, John F Gilmer, An investigation into the effects of ursodeoxycholic acid and derivatives on the golgi apparatus, ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2009, 238, AMER CHEMICAL SOC, 2009 Conference Paper, 2009

Ruiz JF, Radics G, Windle H, Serra HO, Simpliìcio AL, Kedziora K, Fallon PG, Kelleher DP, Gilmer JF, Design, Synthesis, and Pharmacological Effects of a Cyclization-Activated Steroid Prodrug for Colon Targeting in Inflammatory Bowel Disease., Journal of Medicinal Chemistry, 52, (Apr 27.), 2009 Journal Article, 2009

Jones M, Inkielewicz I, Medina C, Santos-Martinez MJ, Radomski A, Radomski MW, Lally MN, Moriarty LM, Gaynor J, Carolan CG, Khan D, O'Byrne P, Harmon S, Holland V, Clancy JM, Gilmer JF., Isosorbide-based aspirin prodrugs: integration of nitric oxide releasing groups., Journal of Medicinal Chemistry, 52, (21), 2009, p6588 - 6598 Journal Article, 2009

Khan D, Gilmer JF, Carolan CG, Gaynor JM, Ryder SA., Pharmacological effects of a novel isosorbide-based butyrylcholinesterase inhibitor., Chemico-Biological Interactions, 175, ((1-3)), 2008, p231-4- Journal Article, 2008

Carolan CG, Dillon GP, Gaynor JM, Reidy S, Ryder SA, Khan D, Marquez JF, Gilmer JF., Isosorbide-2-carbamate Esters: Potent and Selective Butyrylcholinesterase Inhibitors, Journal of Medicinal Chemistry, 51, (Oct 23, (20)), 2008, p6400 - 6409 Journal Article, 2008

Simplício AL, Clancy JM, Gilmer JF., Prodrugs for amines., Molecules, 13, (3), 2008, p519-47 Review, 2008

Carolan CG, Gaynor JM, Dillon GP, Khan D, Ryder SA, Reidy S, Gilmer JF., Novel isosorbide di-ester compounds as inhibitors of acetylcholinesterase, Chemico Biological Interactions, 175, ((1-3)), 2008, p293-7- Journal Article, 2008

Moriarty LM, Lally MN, Carolan CG, Jones M, Clancy JM, Gilmer JF., Discovery of a "true" aspirin prodrug., Journal of Medicinal Chemistry, 51, (24), 2008, p7991 - 7999 Journal Article, 2008

Gilmer, Moriarty, Lally, Gilmer, Efficient Aspirin Prodrugs, 2007 Patent, 2007

Gilmer, Kelleher, Marquez, 'Targeting Pro-Drugs for Treatment of Gastrointestinal Diseases', , 2007, Ireland 2007/0475, Patent, 2007

John F Gilmer, Louise M Moriarty and John M Clancy, Evaluation of nitrate-substituted pseudocholine esters of aspirin as potential nitro-aspirins, Bioorganic and Medicinal Chemistry Letters, 2007 Journal Article, 2007

Simplicio AL, Matias P, Gilmer JF, Clancy JM, Chiral separation and identification of beta-aminoketones of pharmacological interest by high performance liquid chromatography and capillary electrophoresis, Journal of Chromatography A, 1120, (1-2), 2006, p89 - 93 Journal Article, 2006

Simplicio AL, Clancy JM, Gilmer JF, beta-Aminoketones as prodrugs with pH-controlled activation., International Journal of Pharmaceutics, Epub ahead of print, (Dec), 2006 Journal Article, 2006

Gaynor JM, Dillon GP, Reidy S, Gilmer JF., Synthesis and structure activity relationships (SAR) of a new class of potent and selective butyrylcholinesterase inhibitors, Chemical and Biological Interactions, 157-158, 2005, p380-1. Journal Article, 2005

Gilmer JF, Lally MN, Gardiner P, Dillon G, Gaynor JM, Reidy S., Novel isosorbide-based substrates for human butyrylcholinesterase, Chemical and Biological Interactions, 157-158:, 2005, p317-19 Journal Article, 2005

Gilmer JF, Simplício AL, Clancy JM, A new amino-masking group capable of pH-triggered amino-drug release., Eur J Pharm Sci, Mar;24, (4), 2005, p315 - 323 Journal Article, 2005

Kelly JA, Scalabrino GA, Slator GR, Cullen AA, Gilmer JF, Lloyd DG, Bennett GW, Bauer K, Tipton KF and Williams CH, Nanomolar Inhibitors of TRH-degrading ectoenzyme: structure-activity studies with derivatives of Glp-Asn-ProNH2. Structure-activity studies with high affinity inhibitors of pyroglutamyl-peptidase II, Biochem J., Mar 31, 2005 Journal Article, 2005

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 Journal Article, 2004 URL

Simplício AL, Gilmer JF, Frankish N, Sheridan H, Walsh JJ, Clancy JM., Ionisation characteristics and elimination rates of some aminoindanones determined by capillary electrophoresis, Journal of Chromatography A, 1045, (1/2), 2004, p233 - 238 Journal Article, 2004 URL

Mills C, Cleary BJ, Gilmer JF, Walsh JJ, Inhibition of acetylcholinesterase by tea tree oil., Journal of Pharmacy and Pharmacology , 56, (3), 2004, p375 - 379 Journal Article, 2004

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 Journal Article, 2003 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 Journal Article, 2003 URL

GILMER, JF, MORIARTY, LM, LALLY, MN, CLANCY, JM, ISOSORBIDE-BASED ASPIRIN PRODRUGS II. HYDROLYSIS KINETICS OF ISOSORBIDE DIASPIRINATE, EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 16, 2002, p297 - 304 Journal Article, 2002

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 Journal Article, 2002 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 Journal Article, 2001 URL

GILMER, JF, MORIARTY, LM, MCCAFFERTY, DMF, CLANCY, JM, SYNTHESIS, HYDROLYSIS KINETICS AND ANTI-PLATELET EFFECTS OF ISOSORBIDE MONONITRATE DERIVATIVES OF ASPIRIN, EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 14, 2001, p221 - 227 Journal Article, 2001

DAVIS, AP, STEROID-BASED RECEPTORS FOR INORGANIC ANIONS., unknown, 1997, 213, ISI Web of Science, 1997, pp57 - IEC Meeting Abstract, 1997

DAVIS, AP, GILMER, JF, PERRY, JJ, A STEROID-BASED CRYPTAND FOR HALIDE ANIONS, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 35, 1996, p1312 - 1315 Journal Article, 1996

Non-Peer-Reviewed Publications

JJ Salomon, S Etzbach, F Májer, JF Gilmer, CM Lehr, C Ehrhardt, Fluorescent bile acids for the assessment of organic anionic transporting polypeptide (OATP) function, AAPS J, 25th Annual Meeting of the AAPS, Washington, DC, 23-27/10/2011, 13, (S2), 2011, ppT2119 Meeting Abstract, 2011

S Etzbach, JJ Salomon, F Májer, MN Mohd Najib, CM Lehr, JF Gilmer, C Ehrhardt, Fluorescence-labelled bile acids as novel tools to measure organic anionic transporting polypeptide (OATP) function, AAPS Workshop on Drug Transporters in ADME: From the Bench to the Bedside, Bethesda, MD, 14-16/03/2011, 2011, ppW3020 Meeting Abstract, 2011

Gilmer JF, Byrne W, Rynne A, Isosorbide Aspirinate Esters, 1998, WO 9817673 Patent, 1998

Gilmer JF, Byrne W, Cardioactive Aspirinates, 1997, WO 9705128 Patent, 1997

Research Expertise

Description

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

Projects

  • 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
  • Title
    • Probing the interaction of ursodeoxycholic acid with the steroid receptor
  • Summary
    • Ursodeoxycholic acid (UDCA) has been found to act as a bile secretatogue, immunomodulator and inhibitor of cellular apoptosis. There is some evidence that UDCA activates the glucocorticoid receptor binding to a different region of the ligand binding domain to GR agonists such as dexamethasone. Activation of the GR might then result in a differential regulation of gene expression. In addition it is known that some of UDCAs actions are due to suppression of Activator Protein-1 (AP-1) and Nuclear Factor kappa B (NF-κB). Hence UDCA could act as a prototype for the development of a novel and more selective modifier of the GR creating a class of drugs with inflammatory activity but reduced side effects. This project is a collaboration with Aideen Long at the IMI (St James's) and it uses conventional medicinal chemistry structure-function surveys in combination with high throughput screening (Cellomics) and in silico models of the glucocorticoid receptor. Collaborators: Aideen Long, Dermot Kelleher. Recipient: Ruchika Sharma
  • Funding Agency
    • HRB , IRCSET
  • Date From
    • 2006
  • Date To
    • 2016
  • 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

Keywords

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; Pro-drug design for tissue targeting; PRODRUG; RECEPTORS; STEROIDS; Thyrotropin-releasing hormone-degrading ectoenzyme inhibitors in the treatment of CNS disorders

Recognition

Representations

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

Awards and Honours

Visitng Professor in Medicine Chemistry, University of Wurzburg 2014-

Winner, Big Ideas, Enterprise Ireland for Commercialization in The Life Sciences 2010

Memberships

Member of European Federation of Pharmaceutical Scientists


Last updated 9 September 2016 by School of Pharmacy & Pharmaceutical Sciences (Email).