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.

Tiomolibdic acid salt, Bis-choline tetrathiomolybdate (ATN-224, WTX-101), is under investigation as a therapy against different cancers and Wilson’s disease (WD). ATN-224 is a second-generation analog of ammonium tetrathiomolybdate. ATN-224 is a novel copper chelator. ATN-224 inhibits CuZn superoxide dismutase 1 (SOD1) leading to antiangiogenic and antitumor effects. Strategically tailoring combination regimens that include ATN-224 and target ROS may be a viable approach to advance the treatment of melanoma. ATN-224 is in phase III clinical trial for the treatment of Hepatolenticular degeneration. WTX-101 is in phase II clinical trials for the treatment of Wilson's disease. Once daily WTX-101 treatment over 24 weeks improved neurologic disease, hepatic status and copper control in newly diagnosed WD patients. WTX-101 appears well tolerated. Drug-induced, paradoxical, neurological deterioration was not observed. This compound has received orphan drug designation in both the United States and the European Union. WTX-101 was originally discovered by University of Michigan and now is being developed by Wilson Therapeutics by acquisition.

Valopicitabine is a nucleoside analog and the orally bioavailable prodrug of NM107 that competitively inhibits HCV NS5B polymerase, causing chain termination. Valopicitabine had been in phase II clinical trial for once-daily oral treatment of Hepatitis C virus infection. However, because of the overall risk/benefit profile of subjects undergoing clinical trials, further development of the drug has been temporarily placed on hold by the Swiss drug major Novartis and USA-based Idenix Pharmaceuticals company and the FDA.

Obatoclax (GX15-070) is a novel BH3 mimetic pan Bcl- 2 inhibitor. The clinically studied formulation is as obatoclax mesylate (Box 1), a salt. It is only under study as an intravenous preparation. It functions to block BH3-mediated binding of Bcl-2, Bcl-XL, Mcl-1 and A1 to Bax and Bak. Bax and Bak thus are unopposed and able to dimerize to allow initiation of intrinsic apoptosis. Preclinically, obatoclax has been shown to reverse inhibition of Bax or Bak by Bcl-2, Bcl-XL, Bcl-w and Mcl-1. Obatoclax was discovered by Gemin X, which was acquired by Cephalon, which has since been acquired by Teva Pharmaceuticals. Obatoclax had been in phase III clinical trials by Gemin X Biotechnologies (subsidiary of Teva) for the treatment of non-small lung cancer (NSCLC). The compound received orphan drug designation in the U.S. in 2004 for the treatment of chronic lymphocytic leukemia (CLL). However, Teva discontinued the development of obatoclax in 2013.

Amotosalen (S-59, psoralen derivative), a chemical capable of binding to nucleic acids is added to platelets. UVA illumination (320 – 400 nm wavelengths) of amotosalen-treated platelet components induces covalent cross-linking of any nucleic acids to which amotosalen is bound; thereby, preventing further replication. Amotosalen is used in the INTERCEPT process to cross-link DNA and RNA. Amotosalen has protective activity against pathogens such as bacteria, viruses, protozoa, and leukocytes. Prior to administration amotosalen is added to plasma and platelets, then in vivo this agent penetrates pathogens and targets DNA and RNA. Upon activation by ultraviolet A light, amotosalen forms interstrand DNA and RNA crosslinks and prevents replication. Thus, the pathogen-inactivation system using amotosalen/ultraviolet A offers the potential to mitigate the risk of ZIKV transmission by plasma and platelet transfusion. Inactivation of leukocytes can prevent graft versus host disease upon transfusion.

Sparfosate (PALA) is a stable transition state analogue for an aspartate transcarbamylase- cartalyzed reaction with antineoplastic activity. PALA is a potent inhibitor of aspartate transcarbamylase (Ki about 10(-8) M for ACTases of various origins), which in whole cells blocks the de novo synthesis of pyrimidines. Thus PALA inhibits de novo pyrimidine biosynthesis and increases the extent to which fluorouracil metabolites are incorporated into RNA. In vivo, low doses of PALA inhibit whole body pyrimidine synthesis. While this action is cytotoxic in vitro, extensive human testing demonstrates that PALA alone is devoid of selective antitumor activity. Interest in the therapeutic action of PALA derives from the demonstration that its action potentiates the cytotoxicity of several cytotoxic drugs, notably 5-fluorouracil (5-FU). Development of Sparfosate for cancer and Hepatitis B treatment is assumed to have been discontinued.

Ralimetinib (LY2228820), a trisubstituted imidazole derivative, is a potent and selective, ATP-competitive inhibitor of the α- and β-isoforms of p38 mitogen-activated protein kinase. LY2228820 produced significant tumor growth delay in multiple in vivo cancer models (melanoma, non-small cell lung cancer, ovarian, glioma, myeloma, breast). Eli Lilly is developing ralimetinib for the treatment of cancer.

Vinzolidine (also known as LY104208), a semisynthetic vinblastine derivative that was developed as an antitumor agent. Vinzolidine participated in clinical trials phase II in the oral formulation in patients with lymphoma, particularly Hodgkin's disease. In addition, it was studied in patients with Kaposi's sarcoma, non-small cell lung cancer, colorectal cancer, and breast cancer. It was found significant side effects included neurotoxicity and dose-related myelosuppression. As a result, was suggested intravenous route of administration for vinzolidine could be more safely. However, the phase I trial of intravenous vinzolidine was shown no antitumor activity. The further development of this drug was discontinued.

Trioxifene (LY133314) is a selective estrogen receptor modulator (SERM) with competitive binding activity against estradiol for estrogen receptor alpha (ERalpha) and antagonistic activity against ERalpha-mediated gene expression. Trioxifene has demonstrated activity in dimethyl-benzanthracene-induced mammary carcinoma in rats and human breast cancer patients. Trioxifene mesylate, an antiestrogen with a high FR affinity, was developed with the hope of improving the response rate of ER-positive patients, especially those with a borderline concentration of ER in their tumors. When used in vitro and in vivo, trioxifene has been shown to bind to the estradiol receptors with a binding affinity exceeding that of estradiol by a factor 1.7, whereas tamoxifen has a relative affinity of only 0.18 compared with trioxifene.

Nitromiphene (NIT; CI 628) is a triarylethylene antiestrogen shown to be effective in treatment of experimental breast cancer. Nitromiphene is one of the earliest nonsteroidal selective estrogen receptor modulators (SERMs). It is an anti-estrogen capable to translocate the estrogen receptor to the nucleus and to induce the replenishment of the cytosol receptor. Nitromiphene inhibited the uptake of [3H]-estradiol in rat whole homogenates and isolated cell nuclei tissues and the pituitary, and inhibited estradiol-induced female sexual behavior. Nitromiphene has thus been shown to suppress the growth of chemically induced and ransplantedmammary tumors in rodents. Also, Nitromiphene was shown to have potent, prolonged antiuterotropic effects in immature rats. Nitromiphene has been shown to undergo conversion to demethyl Nitromiphene (CI628M), a phenolic metabolite which had greater affinity for estrogen receptors and greater biological potency in vitro than did Nitromiphene. However, the in vivo antiestrogenic effects of Nitromiphene and demethyl Nitromiphene were similar, possibly due to facile O-demethylation of the former compound after administration.