Senicapoc (ICA-17043) is a blocker of Gardos channel, a calcium-activated potassium channel, in the red blood cell. Preclinical studies and studies in transgenic models of Sickle cell disease (SCD) show that inhibition of potassium efflux through the Gardos channel is associated with an increased haemoglobin level, decreased dense cells and decreased hemolysis. Senicapoc is well tolerated when administered to SCD patients and produces dose-dependent increases in hemoglobin and decreases in markers of hemolysis. Senicapoc exerts anti-fibrotic and anti-inflammatory activities. Senicapoc has previously been in Phase III and Phase II clinical trials for the treatment of SCD and asthma, respectively.

Tetrahydrouridine is a potent competitive reversible inhibitor of cytidine deaminase. Tetrahydrouridine can inhibit cell proliferation by regulation of the cell cycle independent of cytidine deaminase (CDA) expression levels. Tetrahydrouridine may be useful for researching potential treatments for high CDA-expressing tumors. Tetrahydrouridine use, alone or in combination with the DNA methyltransferase inhibitor 5-fluoro-2’-deoxycytidine, is being evaluated in animal models and clinical trials for diseases, including cancer and mitochondrial DNA depletion syndrome.

Isobutyramide (VX-366) is an orally available branched chain amide that may offer an alternative to current treatments for beta-hemoglobinopathy. Isobutyramide has been shown to increase fetal hemoglobin (HbF) in patients with beta-hemoglobinopathies. Isobutyramide was originated at the Children's Hospital Oakland Research Institute which, in 1993, granted exclusive worldwide rights for the agent to Vertex. However, development of Isobutyramide has been discontinued for sickle cell anaemia and thalassaemia.

Perflenapent (EchoGen, Sonus Pharmaceuticals, Bothel, WA, USA) is a transpulmonary echocardiographic contrast agent for use in patients with suspected or established cardiovascular disease to provide opacification of cardiac chambers, enhance left ventricular border delineation with resulting improvement in wall motion visualisation. EchoGen comprises liquid droplets of dodecafluoropentane stabilised by polyfluoroalkyl(polyoxyethylene) ethanol and dispersed in an aqueous formulation containing sucrose. Dodecafluoropentane is the chemical name used to reflect the perflenapent/perflisopent mixture. Following activation and administration of EchoGen, dodecafluoropentane microbubbles are formed. EchoGen should only be used in patients where the study without contrast enhancement is inconclusive. The European Commission has approved SONUS Pharmaceuticals' EchoGen (perflenapent emulsion) in all 15 countries of the European Union. EchoGen is a fluorocarbon-based ultrasound contrast agent which has been approved as a transpulmonary echocardiographic contrast agent for use in patients with suspected or established cardiovascular disease who have had previous inconclusive non-contrast studies. Additional approved labeling in the EU states that the use of EchoGen in spectral and color Doppler studies was shown to enhance the visualization of blood flow across mitral, aortic and tricuspid valves in a subset of patients. In 2000 SONUS Pharmaceuticals withdrew the NDA for EchoGen in the USA.

Carbon monoxide (CO) is a colorless, odorless, tasteless, and nonirritating but highly toxic gas generated by both natural and manufactured processes. CO displays many physiological roles in the neuronal, cardiovascular, and immune systems, as well as in the respiratory, reproductive, gastrointestinal, and urogenital apparatus, including anti‐apoptotic, anti‐inflammatory, anti‐oxidant, anti‐proliferative, and vasodilator effects. Although many pathologies, including cancer, hematological diseases, hypertension, heart failure, inflammation, sepsis, neurodegeneration, and sleep disorders, have been linked to abnormal endogenous CO metabolism and functions, CO displays therapeutic actions. CO has demonstrated therapeutic potential against a wide range of human diseases. However, development of CO as a therapeutic agent is severely impeded, primarily due to the lack of pharmaceutically acceptable delivery forms of CO. The therapeutic use of CO is based on (i) the induction or gene transfer of HO‐1, (ii) the inhalation of gaseous CO, and (iii) the use of CO‐releasing molecules (CO‐RMs). There is a large amount of broad preclinical evidence of the benefits of CO in large and small animal models. Importantly, CO is effective both as a prophylactic and as a therapeutic in diverse models, such as malaria, organ transplantation and pulmonary hypertension. Inhaled CO and CO-RMs are in development as therapeutics; inhaled CO is being tested in Phase II clinical trials for kidney transplantation and various CO-RMs are under preclinical evaluation. The precise molecular targets for CO remain unclear with a wide range of evidence for both haem and non-haem targets. A commonality revolves around the contributions of the mitochondria and alterations in cellular bioenergetics. Inhaled CO delivery can be accomplished with an innovative delivery device. In addition strong medicinal chemistry is driving CO-RM development with efforts towards tissue specificity and the appropriate pharmacokinetic and pharmacodynamic profiling. Inhaled CO has found wide applications in basic research in examining CO’s physiological and pathological roles, yet its application in human has many limitations, such as difficulty in precise dose control, lack of portability and inability for targeted delivery, among others. In order to mitigate these limitations, a family of transition metal based CO-releasing molecules (CO-RMs) have been elegantly devised, and have shown CO-associated biological outcomes both in vitro and in vivo. Proterris is developing an inhaled carbon monoxide (CO) therapy for the treatment of idiopathic pulmonary fibrosis (IPF), delayed graft function (DGF), acute kidney injury and renal fibrosis.

Citrulline (name derived from citrullus, the Latin word for watermelon, from which it was first isolated) is an amino acid. It is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine as a by-product of the reaction catalyzed by nitric oxide synthase (NOS) family. Citrulline supplements have been claimed to promote energy levels, stimulate the immune system and help detoxify ammonia (a cell toxin). Citrulline is not involved in protein synthesis. Several pharmacokinetic studies have confirmed that citrulline is efficiently absorbed when administered orally. Oral citrulline could be used to deliver arginine to the systemic circulation or as a protein anabolic agent in specific clinical situations (for example in case of malnourishment), because recent data have suggested that citrulline, although not a component of proteins, stimulates protein synthesis in skeletal muscle through the mammalian target of rapamycin signaling pathway. Citrulline is converted to L-arginine by argininosuccinate synthase. L-arginine is in turn responsible for citrulline's therapeutic effects. Many of L-arginine's activities, including its possible anti-atherogenic actions, may be accounted for by its role as the precursor to nitric oxide (NO).

Doconexent (Docosahexaenoic acid, DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. DHA is widely used as a food supplement, and is beleived to support healthy brain development in young childred, prevent cardiovascular disease and cognitive decline during Alzheimer's disease. Most of these claims, however, were not supported by clinical trials. DHA spray is used as a tanner.

Naproxcinod is the first in the class of CINODs and has been evaluated in preclinical and clinical studies. It is metabolized to naproxen and has been shown to donate nitric oxide in vitro and in vivo. It stimulated the expression of heme oxygenase-mRNA in endothelial cells in vitro, a crucial mediator of antioxidant and tissue-protective actions. In preclinical studies, Naproxcinod has been shown to be analgesic and anti-inflammatory. Naproxcinod dose-dependently displayed a noticeable and significant anti-ischemic effect in reperfused ischemic rabbit hearts and did not exhibit the hypertensive effects of naproxen. In a proof of concept study in 31 healthy volunteers with GI tolerance as the primary endpoint, Naproxcinod caused fewer gastric erosions in both the stomach and the duodenum than naproxen, while 0.2 erosions were found with placebo. Naproxcinod caused less of an adverse effect in intestinal permeability than naproxen and was similar to placebo.