Nemorubicin, a doxorubicin derivative, is a DNA-intercalator, topoisomerase and RNA synthesis inhibitor that was undergoing development with Nerviano Medical Sciences (Nerviano MS; formerly Pharmacia Italia) for the treatment of solid tumours, specifically, the loco-regional treatment of primary liver tumours (hepatocellular carcinoma). The drug is active on tumors resistant to alkylating agents, topoisomerase II inhibitors and platinum derivatives. It works primarily through topoisomerase I inhibition. Of note, Nemorubicin is active in cells with upregulation of the nucleotide excision repair (NER) pathway, where current therapies fail. Nemorubicin is biotransformed in the liver into cytotoxic metabolites that may further contribute to render this drug highly active against primary liver tumors or liver metastases. Clinical trials were conducted in Europe, US and China with Nemorubicin given at different dose-schedules and by different routes of administration: as single agent by systemic IV route, oral route and by intra-hepatic artery (IHA) infusion alone or in combination with cisplatin.

Salirasib or S-trans,trans-Farnesylthiosalicylic acid (FTS) is a salicylic acid derivative with potential antineoplastic activity. It acts as a potent competitive inhibitor of the enzyme prenylated protein methyltransferase (PPMTase), which methylates the carboxyl-terminal S-prenylcysteine in a large number of prenylated proteins including Ras. In such systems, Salirasib inhibits Ras methylation but not Ras farnesylation. Salirasib selectively disrupts the association of chronically active Ras proteins with the plasma membrane. Salirasib competes with Ras for binding to Ras-escort proteins, which possess putative farnesyl-binding domains and interact only with the activated form of Ras proteins, thereby promoting Ras nanoclusterization in the plasma membrane and robust signals. Salirasib was studied in the clinical trials in patients with solid tumors, however its development was discontinued.

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.

Tecalcet (also known as KRN-568; NPS-R-568; R-568), is an oral calcium channel agonist potentially for the treatment of hyperparathyroidism. Calcimimetics, such as Tecalcet, are agonists and activate the calcium channel in a non-competitive fashion. Tecalcet does not compete directly with calcium that activates the receptor through binding in the extracellular domain of these receptors, but rather, calcimimetics such as Tecalcet, bind allosterically in the seven transmembranes to ‘sensitize’ the receptor to extracellular calcium. Tecalcet acts as an agonist of the calcium receptors of the parathyroid cells, causing a decrease in PTH release. Tecalcet also acts on the parafollicular cells (C-cells) of the thyroid gland, resulting in an increase in calcitonin release. These effects ultimately lead to a decrease in plasma calcium concentrations. Studies in rats have shown that oral administration of R-568 at doses ranging from 3 to 100 mg/kg caused a rapid (<30 minutes) decrease in plasma PTH concentrations and an increase in calcitonin concentrations, accompanied by a dose-dependent decrease in calcium concentrations. Tecalcet had been in phase II clinical trials by for the treatment of hyperparathyroidism, postmenopausal osteoporosis and rheumatic disorders in Japan and US. Development of Tecalcet has been discontinued.

Nelivaptan is a selective, orally active, non-peptide vasopressin receptor antagonist selective for the V1B subtype. It showed promise in preclinical animal models and advanced to phase II clinical trials for the treatment of anxiety and depression; however, in 2008, Sanofi-Aventis announced that further development of this drug had been halted.

Alvespimycin (17-desmethoxy-17-N,N-dimethylaminoethylamino-geldanamycin) (17-DMAG; NSC 707545) is an inhibitor of the molecular chaperone heat shock protein HSP90. Alvespimycin is a derivative of antineoplastic benzoquinone antibiotic geldanamycin. Alvespimycin binds to HSP90, a chaperone protein that aids in the assembly, maturation and folding of proteins. Subsequently, the function of Hsp90 is inhibited, leading to the degradation and depletion of its client proteins such as kinases and transcription factors involved with cell cycle regulation and signal transduction. Alvespimycin was studied in clinical trials for the treatment of solid tumors and hematologic malignancies however its development was discontinued.

Varlitinib (Alternative Names: ARRY-334543; ARRY-543; ASLAN-001; Varlitinib tosylate) is a small molecule based reversible pan-HER inhibitor of EGFR, HER2 and HER4. In response to the binding of various ligands, these kinases undergo heterodimerisation and homodimerization, resulting in activation of numerous growth factor signaling pathways, by inhibiting the activation of the HER receptors via drug, effects such as shrinkage of the tumor and longer survival can be anticipated. In a large variety of cancers, the overexpression and/or constitutive activation of EGFR and HER2 are often observed and frequently correlate with poor clinical prognosis. Licensed from Array BioPharma with global rights for all indications, varlitinib is being developed as first-in-class drug for cholangiocarcinoma, gastric and colorectal cancer, and as best-in-class drug for breast cancer.

Rupintrivir is a peptide aldehyde that targets the human rhinovirus (HRV) 3C proteinase enzyme and has the potential for the treatment of the common cold. Rupintrivir is derived from AG-6084 - in order to develop human rhinovirus 3C protease inhibitors with improved pharmacological properties, Agouron replaced the backbone amide moiety of the series which yielded AG-6084, with a ketomethylene isostere. A phase II efficacy study has been completed in healthy patients infected with the rhinovirus. Ruprintrivir was well tolerated; blood-tinged mucus and nasal passage irritation were the most common adverse effects reported. Pharmacokinetic analysis of plasma and nasal ruprintrivir concentrations revealed intranasal drug residence with minimal systemic absorption. The fact that rupintrivir is active against noroviruses belonging to genogroup I (Norwalk virus), genogroup V (murine norovirus), and the recombinant 3C-like protease of a GII norovirus suggests that the drug exerts cross-genotypic anti-norovirus activity and will thus most likely be effective against the clinically relevant human norovirus strains. Rupintrivir is also a high affinity inhibitor of Enterovirus-71 3C protease.

Org 25935 (SCH 900435) is a synthetic drug developed by Organon International, which acts as a selective inhibitor of the glycine transporter GlyT-1. In human trial for prevention of relapse in alcohol-dependent patients in Org 25935 demonstrated no benefit over placebo in preventing alcohol relapse. Org 25935 was tested as an adjunctive treatment to atypical antipsychotics in predominant persistent negative symptoms of schizophrenia, where it did not differ significantly from placebo in reducing negative symptoms or improving cognitive functioning. Clinical trials against panic disorder did not show any benefit compared to placebo.

TNP-470 (AGM-1470, (3R,4S,5S,6R)-5-methoxy-4- [(2R,3R)-2-methyl-3-(3-methyl-2-butenyl) -oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl) carbamate) is an anti-angiogenic, semisynthetic analogue of fumagillin, a known antibiotic secreted by the fungus Aspergillus fumigatus fresenius, which is under clinical development for the treatment of cancer by Takeda Chemical Industries Ltd. in Japan and TAP Pharmaceuticals, Inc. in the United States. TNP-470 binds to and irreversibly inactivates methionine aminopeptidase-2 (MetAP2), resulting in endothelial cell cycle arrest late in the G1 phase and inhibition of tumor angiogenesis. This agent may also induce the p53 pathway, thereby stimulating the production of cyclin-dependent kinase inhibitor p21 and inhibiting angiogenesis. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose-limiting toxicity (DLT). TNP-470 is being evaluated in Phase I-II trials in the US in patients with Kaposi’s sarcoma, cervical cancer, breast cancer, brain cancer, prostate cancer and renal cell carcinoma.