Professor John Gilmer

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

POC, Tech Dev, Innovations

Project Type

applied

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

Project Type

Basic

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

Project Type

Basic Research