LAFLUNIMUS is an immunomodulator with anti-inflammatory activities. It inhibits prostaglandin endoperoxide H synthases 1 and 2 in vitro and in vivo. It also acts as an immunosuppressive agent being an inhibitor of mitochondrial dihydroorotate dehydrogenase and concomitant reducing agent of pyrimidine nucleotide pools.

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.

S-nitrosoglutathione (GSNO) is an endogenous S-nitrosothiol that acts as a NO pool. The level of GSNO is tightly regulated by S-nitrosoglutathione reductase (GSNOR), an enzyme that degrades GSNO. GSNOR inhibitors offer a potentially promising option for the management of pre-eclampsia, a cause of maternal death and of perinatal morbidity. The GSNO treatment of traumatic brain injury improved neurobehavioral functions. GSNO can increase the expression of certain proteins at concentrations present in the normal human airway. GSNO has an important role in regulating respiratory function (breathing) and preventing inflammation in the respiratory tract, that is why this compound participated in phase I clinical trials for patients with asthma. In addition, GSNO was studied in the cystic fibrosis airway. The obtained results have shown that GSNO replacement therapy could be an effective treatment. In addition, GSNO was investigated for patients with chronic obstructive pulmonary disease.

CPI-613 is a lipoate derivative synthesized to be catalytically inert but to potentially mimic lipoate catalytic intermediates. The drug is in phase II of clinical trials for the treatment of Myelodysplastic syndromes; Pancreatic cancer; Small cell lung cancer; Solid tumors; Bile duct cancer; Acute Myeloid leukemia. The mechanism of CPI-613 action can be explained by (I) inhibition of tumor cell pyruvate dehydrogenase complex (PDC) through activation of pyruvate dehydrogenase kinases leading to inactivating phosphorylation of the E1alpha-subunit of PDC; and (II) inhibition of alpha-ketoglutarate dehydrogenase.

Netazepide (YF476) is an orally active, benzodiazepine type, selective cholecystokinin B receptor (CCKBR; CCK2R; gastrin receptor) antagonist with potential gastric acid reducing and antiproliferative activity. Upon administration, netazepide, selectively binds to and blocks the CCKBR, thereby preventing the binding of gastrin and cholecystokinin. This may prevent gastric neuroendocrine enterochromaffin-like (ECL) cell-induced secretion of histamine, ultimately preventing gastric acid secretion from adjacent parietal cells. In addition, YF476 may inhibit ECL cell proliferation and ECL-derived gastric carcinoids. Netazepide has been used in trials studying the prevention and treatment of dyspepsia, hypergastrinaemia, barrett's esophagus, ECL-cell hyperplasia, and rebound hyperacidity, among others. Netazepide once daily for 12 weeks reduced the number of tumours and size of the largest one in 16 patients with autoimmune chronic atrophic gastritis (CAG), achlorhydria, hypergastrinaemia and multiple gastric neuroendocrine tumours (type 1 gastric NETs), and normalized circulating chromogranin A (CgA) produced by enterochromaffin-like cells, the source of the tumours.

Bardoxolone methyl, the C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) known as CDDO-Me or RTA 402, is one of the derivatives of synthetic triterpenoids. Bardoxolone methyl directly blocks IKKbeta activity and thereby the NF-kappaB pathway by interacting with Cys-179 in the IKKbeta activation loop. Binding of bardoxolone methyl to Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) disrupts its critical cysteine residues, leading to the release of the nuclear factor erythroid 2-related factor 2 (Nrf2), which hinders its ubiquitination and finally leads to its stabilization and nuclear translocation. In the nucleus, Nrf2 activates the transcription of phase 2 response genes, leading to a coordinated antioxidant and anti-inflammatory response. In addition, it acts as an antagonist of the peroxisome proliferator-activated receptor gamma. Through Keap1/Nrf2 and nuclear factor-κB pathways, this agent can modulate the activities of a number of important proteins that regulate inflammation, redox balance, cell proliferation and programmed cell death. This agent is generally well tolerated, but it may increase adverse cardiovascular events. Presently, it is being further tested for the treatment of patients with chronic kidney disease, cancer, and pulmonary arterial hypertension.

Sabarubicin (previously known as MEN-10755), a disaccharide analog of doxorubicin that was developed by Menarini Pharmaceuticals for the treatment of solid tumors, including small cell lung cancer and prostate cancer. Sabarubicin exhibits a superior antitumor efficacy, presumably related to the activation of p53-independent apoptosis. The drug participated in phase II clinical trials to study its effectiveness in treating patients who have progressive prostate cancer that has not responded to hormone therapy and in chemotherapy-naive patients with extensive stage small cell lung cancer. On 21 December 2004, the European Commission granted the orphan designation to Menarini for sabarubicin for the treatment of small cell lung cancer.

Arbaclofen (STX209, R-baclofen), a selective agonist of GABA-B receptors, has been investigated in clinical trials for the treatment of autism spectrum disorder ASD, phase II and for the treatment of patients with fragile X syndrome in phase III. As a result, the drug did not meet the primary outcome of improved social avoidance in FXS in either study. In spite of positive results in some children with ASD, further study will be needed to replicate and extend these initial findings. Arbaclofen has also been investigated in phase III clinical trials as a treatment for spasticity due to multiple sclerosis.

Liarozole is an imidazole-containing compound that inhibits the cytochrome P-450-dependent metabolism of all-trans-retinoic acid (RA). Liarozole, a retinoic acid (RA) metabolism-blocking agent (RAMBA) in clinical development, has been granted orphan drug designation for congenital ichthyosis by the European Commission and the U.S. Food and Drug Administration. Later, based on the mixed results from a phase II/III trial of liarozole for the treatment of ichthyosis, Barrier decided to discontinue the development of liarozole. Liarozole displays antitumor activity against androgen-dependent and independent rat prostate carcinomas.A large phase III international study was completed comparing liarozole 300 mg twice daily with cyproterone acetate (CPA) 100 mg twice daily in a total of 321 patients with metastatic prostate cancer in relapse after first-line endocrine therapy. The results indicate that liarozole might be a possible treatment option for prostate cancer (PCA) following failure of first-line endocrine therapy.

Perifosine is an orally active alkyl-phosphocholine compound with potential antineoplastic activity. Perifosine is an Akt inhibitor, which targets the pleckstrin homology domain of Akt, thereby preventing its translocation to the plasma membrane. Perifosine exerts Akt-dependent and Akt-independent effects, and although many preclinical studies have documented Akt inhibition by perifosine, clinical validation of these findings is lacking. Perifosine is in phase II and III clinical trials for the treatment of neuroblastoma, glioblastoma multiforme and other solid tumors.