Cidoxepin is the cis-isomer of the widely prescribed tricyclic compound doxepin. Commercial preparations of the tricyclic anti-depressant doxepin contain 15% of the more active cis-doxepin and 85% of the trans-isomer. Elorac, Inc., a rapidly growing specialty pharmaceutical company focused on the treatment of dermatological disorders, is pleased to announce that it has acquired worldwide rights to the active agent Cidoxepin from Gideon Pharmaceuticals. Cidoxepin appears to be much more potent than doxepin while having less sedative and cholinergic side effects. Elorac plans to develop oral formulations of the drug to treat urticaria and topical formulations for treatment of atopic and contact dermatitis.

Halofuginone is a low molecular weight quinazolinone alkaloid, and a potent inhibitor of collagen alpha1(I) and matrix metalloproteinase 2 (MMP-2) gene expression. Halofuginone also effectively suppresses tumor progression and metastasis in mice. Halofuginone is a potent inhibitor of collagen a1(I) and matrix metalloproteinase 2 (MMP-2) gene expression. Halofuginone also suppresses extracellular matrix deposition and cell proliferation. Also was shown that halofuginone increased apoptosis in α smooth muscle actin- and prolyl 4-hydroxylase β-expressing cells in mdx diaphragm and in myofibroblasts, the major source of extracellular matrix. The profound antitumoral effect of halofuginone is attributed to its combined inhibition of tumour-stromal support, vascularization, invasiveness, and cell proliferation. HT-100 (delayed-release halofuginone), currently in clinical phase 1b/2a in five U.S. hospitals, is a small molecule drug candidate taken orally for the treatment of Duchenne muscular dystrophy (DMD) patients primarily through its ability to reduce fibrosis and inflammation and promote muscle fiber regeneration. The medicine candidate has been granted orphan drug designation in the U.S. and the EU — meaning it has been commercially undeveloped due to its limited profitability — and fast-track designation in the U.S. — an FDA process that aims to facilitate the development and patients’ reach to novel therapies for unmet medical needs.

Hycanthone is a thioxanthene derivative of lucanthone with anti-schistosomal activity and potential antineoplastic activity. It was clinically available for the treatment of human schistosomiasis. Anti-helmintic action relies on its ability to inhibit worm monoamine oxidase and cholinesterases. Hycanthone produced immediate side effects such as hepatotoxicity and gastrointestinal disturbances, and was consequently withdrawn. Hycanthone inhibits apurinic endonuclease-1 (APE1) by direct protein binding. Hycanthone was used in the 1980s as antitumor agents, it was pulled out of Phase II trials.

Traxoprodil (CP-101,606) is a potent, selective N-Methyl-D-aspartate (NMDA) receptor (NR2B subunit) antagonist under development by Pfizer for its potential as a neuroprotectant in head injury and neurodegenerative disease. It is in phase II trials in the US and in phase I in Japan for the potential treatment of head injury, such as, Depressive Disorder, Major and Parkinson's Disease. CP-101,606 does not protect against glutamate-induced neurotoxicity in cultured cerebellar neurons, up to a dose of 10 uM. These results are consistent with CP-101,606 being a potent NMDA antagonist, selective for the type of NMDA receptor associated with the hippocampus. Some further investigation revealed that CP-101,606 was associated with a dose-related dissociation and amnesia. These results support the hypothesis that glutamate antagonists may be useful antidyskinetic agents. However, future studies will have to determine if the benefits of dyskinesia suppression can be achieved without adverse cognitive effects.

Triciribine is a purine analogue which inhibits DNA and protein synthesis, it is a synthetic tricyclic nucleoside which acts as a specific inhibitor of the Akt signaling pathway. It selectively inhibits the phosphorylation and activation of Akt1, -2 and -3 but does not inhibit Akt kinase activity nor known upstream Akt activators such as PI 3-Kinase and PDK1. It inhibits cell growth and induces apoptosis preferentially in cells that express aberrant Akt1. In whole cells triciribine is phosphorylated by adenosine kinase which may be necessary for its activity. Triciribine is a cancer drug which was first synthesised in the 1970s and trialled clinically in the 1980s and 1990s without success. Following the discovery in the early 2000s that the drug would be effective against tumours with hyperactivated Akt, it is now again under consideration in a variety of cancers. As PTX-200, the drug is currently in two early stage clinical trials in breast cancer and ovarian cancer being conducted by the small molecule drug development company Prescient Therapeutics.

NT-702 (parogrelil hydrochloride) is a novel phosphodiesterase 3 (PDE) inhibitor, and being developed for the treatment of intermittent claudication (IC) in patients with peripheral arterial disease. In Japan, Phase 2 studies are being conducted for intermittent claudication caused by arteriosclerosis obliterans, intermittent claudication caused by spinal canal stenosis, and asthma. In the USA, a Phase 2 study for intermittent claudication caused by arteriosclerosis obliterans has been successfully completed. Also was shown, that NT-702 has an anti-inflammatory effect as well as a bronchodilating effect and might be useful as a novel potent therapeutic agent with both a bronchodilating and an anti-inflammatory effect.

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.

Semapimod (CNI-1493) is a cytokine inhibitor and synthetic guanylhydrazone mitogen-activated protein kinase blocker, is being developed by Cytokine PharmaSciences as a potential treatment for Crohn's disease and other inflammatory conditions. As of December 2001, a phase I study demonstrating the safety of the compound had been completed and phase II trials for psoriasis and Crohn's disease were ongoing. In April 2003, preclinical and early clinical studies were underway for a variety of indications, including congestive heart failure and pancreatitis. Semapimod inhibits activation of p38 MAPK and NF-κB and induction of cyclooxygenase-2 by TLR ligands, but not by IL-1β or stresses. Semapimod inhibits TLR4 signaling (IC50 ≈0.3 umol) and acts by desensitizing cells to LPS; it fails to block responses to LPS concentrations of ≥5 ug/ml. Semapimod had been in phase II clinical trials by Ferring Pharmaceuticals for the treatment of Crohn's disease. However, this research has been discontinued. Semapimod is in phase I clinical trials for the treatment of autoimmune disorders and inflammation.

Brequinar is a synthetic quinolinecarboxylic acid analogue with antineoplastic properties. Brequinar inhibits the enzyme dihydroorotate dehydrogenase, thereby blocking de novo pyrimidine biosynthesis. This agent may also enhance the in vivo antitumor effect of antineoplastic agents such as 5-FU. Brequinar had been in phase II clinical trials by Bristol-Myers Squibb for the treatment of cancer and transplant rejection. However, this research has been discontinued. Brequinar had been also in preclinical studys for the treatment of cytomegalovirus infections. However, this research has been discontinued.

Piboserod (SB 207266) is a selective 5-HT(4) receptor, antagonist. The 5-HT4 receptor antagonists are thought to antagonize both the ability of serotonin to sensitize the peristaltic reflex and 5-HT-induced defecation, at least in animal studies. As 5-HT4 receptors are present in human atrial cells and when stimulated may cause atrial arrhythmias, piboserod was under investigation in clinical trials for atrial fibrillation. In addition, GlaxoSmithKline studied the drug for the management of irritable bowel syndrome. Nevertheless, development both indications had been discontinued. Piboserod has successfully passed phase II clinical trials for the treatment of patients with congestive heart failure.