NicOx Nitric Oxide Donating Technology

	NicOx Nitric Oxide-donating technology


	Nitric oxide plays a critical role in many processes in the human body, acting as a messenger molecule and conveying biochemical signals in a range of tissues, from the cardiovascular system, to the central nervous and immune systems. There is significant evidence that certain diseases are related to a deficiency in the production of nitric oxide. This creates the possibility that new drug treatments can be developed which supplement nitric oxide exogenously when the body cannot generate sufficient amounts to allow normal biological functions.



	Rationale for NO-donation The solid biological basis for the use of nitric oxide replacement therapy is supported by the fact that organic nitrates and nitrate esters have been used for over a century in the treatment of angina pectoris (chest pain due to insufficient blood supply to an area of the heart muscle). However, existing drugs have a number of drawbacks related to the rapid release of nitric oxide that can cause side effects such as headaches and reduce effectiveness due to tolerance. For example, despite the strong biological rationale for using nitric oxide to prevent platelet activation and clot formation and the evidence that nitric oxide plays a role in the control of blood pressure, existing compounds are not widely used in these indications due to the problems of rapid nitric oxide release. NO-donation is applied to proven drug molecules NicOx’ technology involves grafting a nitric oxide-donating chemical group onto an existing drug molecule, using a linker. This forms a new chemical entity which can be patented. NicOx believes this technology has the potential to improve the efficacy and safety of existing drug molecules, or even change their activity to allow their use in completely new therapeutic areas. Indeed, a variety of experimental and clinical studies have confirmed this initial hypothesis. When these compounds are absorbed by the human body they are cleaved to yield the drug and the nitric oxide-donating group still attached to the linker. The linker molecule then circulates in the body and delivers nitric oxide in a sustained and controlled manner to the tissues and therefore NicOx’ compounds do not cause the side effects and tolerance issues associated with rapid nitric oxide release. Focus on cardiometabolic and inflammatory disorders NicOx’ research strategy is to focus on those areas where its nitric oxide-donating technology can bring the greatest benefits with the lowest risk and clearest development pathway. Based on the experience that NicOx has gained over the last few years, the Company has decided to focus its research activities in the cardiometabolic and inflammatory therapeutic areas. These two domains have been identified as key targets on the basis of a wealth of data, from both basic and clinical research, showing that exogenous supply of nitric oxide has a beneficial effect on endothelial dysfunction and tissue inflammation. NicOx’ research program aims to improve current ‘best in class’ drugs through nitric oxide-donation, with the goal of developing new drug candidates which can be developed by NicOx, either alone, or together with a partner. Scientists in NicOx’ research laboratories are highly experienced in the synthesis and testing of nitric oxide-donating compounds. Obtaining compounds with optimal pharmacological and pharmacokinetic profiles involves considerable know-how which relates to the particular linker-compounds that are used. For example, the release of nitric oxide from the linker is mediated by the body’s own enzymes and the rate of this process is influenced by the particular form of the linker. Identifying new NO-donating drug candidates Once a nitric oxide-donating molecule has been synthesized this is initially tested to determine the amount of nitric oxide that is released from the compound and its rate of release. This is achieved using a variety of laboratory equipment, together with biological tests that follow biomarkers such as cyclic GMP levels, which are relevant to the nitric oxide-mediated activity (cyclic GMP is a cellular messenger induced by nitric oxide). Compounds with the right profile are then entered into the subsequent step which involves assessing their biological properties in cellular and in vivo disease models relevant to the target pathology in humans. Each new compound is typically compared to a reference drug, with the aim of assessing whether nitric oxide-donation provides advantages, such as a potentially improved activity or safety profile, or completely new activities which suggest it could fulfill an unmet medical need. The profile of each drug candidate that emerges from research is carefully assessed to determine whether its data package is sufficiently compelling to justify its subsequent preclinical and clinical development.