Synthesis and Biology of Prostanoids

Prostanoids, consisting of prostaglandins, prostacyclins, and thromboxanes are an important class of local hormone-like chemical messengers, which are responsible for a diverse range of biological activities in mammalian tissues. Some synthetic analogues of prostaglandins (PG) are 'billion dollar' drugs e.g. latanoprost, which is used to treat glaucoma. However, since these complex molecules cannot be isolated from natural sources in sufficient quantities, they have to be synthesised (20 steps) at considerable cost. We have developed a dramatically shorter route to this class of compounds (7 steps) and demonstrated a gram scale synthesis of PGF2alpha 6, which could substantially reduce the cost of manufacture of prostaglandins. We now plan to broaden the reach of this chemistry. Just as the Corey lactone has been used to prepare other prostanoids, we believe that our key enal intermediate, used in the synthesis of the prostaglandin PGF2alpha, is even better placed to access all of the other prostanoids more efficiently. We therefore plan to prepare key members of each class of prostanoids thereby demonstrating its potential to access the whole family of prostanoids. Many of the prostanoids are highly unstable (prostacyclins, thromboxanes) and so we will prepare fluorinated analogues that are stable. We will demonstrate the power of the key enal intermediate used in the synthesis of PGF2alpha to access the remaining prostanoids in a substantially shorter number of steps than has been previously reported.

This proposal not only seeks to prepare these important molecules more efficiently but it also seeks to study the pharmacological properties of the molecules we make. For this, we will use human platelets, which are essential for primary haemostasis but also play an important role in thrombosis and cardiovascular disease. We will determine the anti-platelet effects of the fluorinated prostacyclin analogue and beraprost 9 on various functional platelet responses and intracellular signalling pathways and compare this to the effect of the well-studied PGI2 analogue iloprost. When platelets become activated, they also release TxA2, which further activates and recruits platelets to the growing thrombus. The pharmacological properties of the TxA2 analogues 11/12 on platelet functional and intracellular signalling pathways will be determined and directly compared to the TxA2 analogue U46619.

Due to the important role of platelets in cardiovascular disease, patients at risk of thrombotic events are routinely prescribed anti-platelet drugs that interfere with the amplification of platelet function. The first line of treatment is aspirin, a drug that inhibits TxA2 production in platelets by blocking cyclooxygenase activity. However, its use is associated with undesirable adverse effects such as gastropathies and gastric ulcers, as it inhibits the production of all prostanoids. We therefore propose here to remove the agent, thromboxane A2 as it is produced, by developing a humanised antibody-based drug that targets TxA2 itself. The advantages of this approach are that the likelihood of side effects is significantly reduced, as we are not blocking mechanisms for the production of other prostanoids.

The production of key members of the different classes of prostanoids through a dramatically shorted route will therefore not only result in more efficient production of clinically and academically relevant prostanoids, but also facilitate the development of novel anti-thrombotic approaches in the treatment of cardiovascular disease.

This proposal seeks to develop new shorter routes to synthesize medicinally important prostanoids (section A) and develop a novel therapeutic approach in the treatment of cardiovascular disease (section B). Cardiovascular disease is the main cause of death in the UK and accounted for almost 180,000 deaths in 2010 - around one in three of all deaths that year. The main forms of CVD are coronary heart disease and stroke. CVD is the leading cause of death in the developed world and so research in this field has an incomparable long-lasting, high societal impact nationally, and globally. We have a chance of making a contribution to this highly important healthcare area by making antibodies to TxA2. It would be an alternative to aspirin but without the side effects.

The whole family of clinically used PG drugs (around 30 members) have combined annual sales of >$10bn pa. PGs are highly costly and take around 20 steps to prepare. Some synthetic analogues of prostaglandin (PG) are 'billion dollar' drugs e.g. latanoprost 7, which is used to treat glaucoma. A reduction in the number of steps will not only reduce the cost, and so make it more available to a larger proportion of the population, but also make larger scale production feasible. For example, a new topical application of PGF2 alpha analogues for reduction of adipose tissue discovered by Topokine Therapeutics is set to dwarf these numbers and, if successful in reaching the market, will require a >1000 fold increase in volume of production of PGs (see Pathways to Impact Section). Indications are that PGs could also find application in the treatment of diabetes so again large volumes will be required because this is such an endemic condition. Thus, this research would have a major impact not only in the UK but world-wide.

In addition, another key output from the grant will be a cohort of highly skilled and accomplished young researchers, who will have had the opportunity to make contributions and gain expertise in a highly challenging and rewarding area of contemporary science and so support the needs of the academic and industrial sectors. The UK chemical and pharmaceutical industries, who are major contributors to UK wealth, rely on this output.

Finally, we expect this work into fundamentally important molecules, which could find new applications in medicine and open up new fields of research, to lead to a significant impact in the field. This would result in attracting high quality of individuals from abroad to our research group. This is likely to benefit UK in having a greater pool of highly talented and highly trained scientists that UK plc can potentially recruit from.