Nitroarginine (LNNA), an analog of L-arginine, is a competitive inhibitor of nitric oxide synthase which has been shown to prevent glutamate toxicity. Nitroarginine has been experimentally tested for its ability to prevent ammonia toxicity and ammonia-induced alterations in brain energy and ammonia metabolites. The Kd value (k(off)/k(on)) of bovine brain cNOS for LNNA was 15 nM. In contrast to the potent and slow onset of LNNA inhibition of brain cNOS, LNNA inhibition of inducible mouse macrophage NOS (iNOS) was weaker (Ki = 4.4 uM) and rapidly reversible. Thus, LNNA was a 300-fold more potent inhibitor of bovine brain cNOS than mouse macrophage iNOS. By inhibiting nitric oxide synthase LNNA causes the selective reduction of blood flow to tumor cells. Despite the potential of LNNA to function as an adjuvant in cancer therapies, its poor solubility and stability have hindered the development of an injectable formulation of LNNA that is suitable for human administration.

Varespladib (LY315920; A-001) is a potent and selective inhibitor of IIa, V, and X isoforms of human non-pancreatic secretory phospholipase A2 with nM IC50. The molecule acts as an anti-inflammatory agent by disrupting the first step of the arachidonic acid pathway of inflammation. Varespladib methyl is being developed by Anthera Pharmaceuticals Inc for the potential treatment of coronary artery disease, acute coronary syndrome and inflammation. Varespladib methyl is a prodrug that is rapidly metabolized to varespladib, and both compounds are able to potently inhibit the enzymes of the human secretory phospholipase groups. Phase II clinical trials of varespladib methyl in patients with coronary artery disease, rheumatoid arthritis, asthma and ulcerative colitis revealed that the drug was well tolerated. Varespladib methyl did not demonstrate a good efficacy profile in patients with rheumatoid arthritis, asthma and ulcerative colitis; whereas in patients with coronary artery disease, varespladib methyl consistently reduced LDL-cholesterol levels, (elevated LDL-cholesterol levels are a marker of increased cardiovascular risk). Varespladib methyl could represent a novel therapy for the treatment of cardiovascular disease, although the efficacy, safety profile and advantages of this drug compared with existing therapeutic options would need to be established in upcoming phase III trials.