Ref document number : Country of ref document : EP. Kind code of ref document : A1. Country of ref document : AU. Date of ref document : Kind code of ref document : A. Ref country code : DE. The present invention provides organic compounds which are capable of releasing carbon monoxide under physiological conditions or pH trigger, and to the use of such compounds for conditioning a cell, tissue or organ, for example, to protect against ischaemic injury during a transplant event.
This disclosure relates to norbornenone compounds, which are capable of releasing carbon monoxide. This disclosure also relates to compositions and formulations comprising the norbornenone compounds. The endogenous existence of carbon monoxide CO -activated protective signalling pathways, including vasodilatory, antiapoptotic, antithrombotic, anti-inflammatory and immunomodulatory, has previously been established.
Delivery of CO gas at low concentrations protects organs from ischaemic injury by decreasing cell death and most significantly inducing a preconditioning response. Carbon monoxide has been found to bind to hemoproteins, such as, myoglobin, soluble guanylate cyclase sGC , inducible nitric oxide synthase, cytochrome p, cytochrome-c oxidase, NADPH oxidase and the parent enzyme heme oxygenase. This CO interaction can modulate the activity or level of expression of these key protein targets to produce a plethora of downstream signalling events.
The antiinflammatory effects of CO are mediated by p38 MAPK signalling and inhibition of the potent pro-inflammatory damage recognition molecule HMBG 1 results in a reduction of proinflammatory cytokines, such as TNF-a, and increase in the expression of the antiinflammatory interleukin The protective and physiological effects of low levels of CO have been studied in a number of both animal and clinical models with the literature extensively reviewed 1.
The results of previous studies have been so compelling that the FDA has granted approval for the application of low dose CO gas in a range of clinical trials such as CO gas delivery by inhalation in heart valve replacement surgery 2 and in renal transplant procedure recipients 3. Inhalation of CO ppm in chronic obstructive pulmonary disease patients, reduced sputum neutrophils and improved bronchial responsiveness.
