SQ-109 is a [1,2]-diamine-based ethambutol (EMB) analog developed for the treatment of tuberculosis. SQ109 acts by inhibiting MmpL3, a transporter of trehalose monomyclate, which is an important component of cellular wall. The drug was investigated as a monotherapy or in combination with rifampicin in phase II clinical trials in pulmonary tuberculosis patients. The clinical trials, however, did not demonstrate activity of SQ-109 alone or its ability to enhance the activity of rifampicin.

Latrunculin A is a naturally occurring toxin that can be purified from the red sea sponge Latrunculia magnifica. It disrupts actin polymerization and prevents mitotic spindle formation; therefore preventing proper cellular replication. It was discovered that latrunculin A has strong anticancer effects, and it was investigated as a treatment candidate for peritoneal dissemination of gastric cancer.

Sotrastaurin, an orally-active, first-in-class immunomodulator, is under development by Novartis for the treatment of uveal melanoma and diffuse-large B-cell lymphoma. Sotrastaurin is a low molecular mass synthetic compound that potently inhibits the PKC α, β and the θ isoforms resulting in selective NF-κB inactivation. Sotrastaurin is a potent and selective pan-PKC inhibitor, mostly for PKCθ with Ki of 0.22 nM in a cell-free assay. Inhibition of PKC beta in B-cells results in prevention of NF-kB-mediated signaling and down regulation of NF-kB target genes. This may eventually lead to an induction of G1 cell cycle arrest and tumor cell apoptosis in susceptible tumor cells. This agent may act synergistically with other chemotherapeutic agents. PKC, a family of serine/threonine protein kinases overexpressed in certain types of cancer cells, is involved in cell differentiation, mitogenesis, inflammation, and the activation and survival of lymphocytes. Sotrastaurin is currently in phase II trials by Novartis for the treatment of large B-cell lymphoma and uveal melanoma. Sotrastaurin was in Phase II of clinical development for the prevention of acute rejection after solid organ transplantation and psoriasis, but this reseach had being discontinued.

Indanidine is a selective and effective α2-antagonist, α1-partial agonist patented by pharmaceutical company Siegfried A.-G as a low toxic compound with direct hypotensive action. Indanidine does not penetrate the blood-brain barrier, does not induce drug-metabolizing enzymes in the liver, does not cause behavioral changes.

Fadolmidine (MPV 2426) is an alpha2-adrenoceptor agonist. Fadolmidine displayed high affinity and full agonist efficacy at all three human alpha2-adrenoceptor subtypes (A, B and C). Various preclinical models of pain have been employed and have demonstrated fadolmidine potential as an analgesic, including its potential for use in neuropathies and post-operative pain. A Phase II clinical trial successfully demonstrated that intrathecal fadolmidine, in combination with bupivacaine, produced analgesic effects compared to bupivacaine alone in bunionectomy patients.

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.

Frakefamide is a tetrapeptide with an amide function at the C-terminus. The amino acid sequence of frakefamide is L-tyrosyl-D-alanyl-p-fluoro-L-phenylalanyl-Lphenylalaninamide. Hence, it contains both natural and unnatural R-amino acids. Frakefamide has shown interesting properties for use in acute and chronic pain treatment. It acts as a selective agonist on mu-opioid receptors and belongs to the dermorphin peptide family. It has been shown to be a potent peripherally acting analgesic in rats and humans. However, frakefamide had been found to have "unexpected results" in Phase II trials and AstraZeneca offered to hand the drug back.

Siguazodan is a selective inhibitor of phosphodiesterase 3. It caused significant increases in cardiac output and stroke volume. It is orally active inotropic/vasodilator agent with a sustained duration in vivo. Siguazodan has potential utility in the treatment of congestive heart failure. Siguazodan has anti-platelet actions over the same concentration range that it is an inotrope and vasodilator. Siguazodan caused bronchodilation. In combination with phosphodiesterase 4, it may be useful in the therapy of asthma.

Vapitadine (R129160; Hivenyl™) is an antihistamine that Barrier Therapeutics is developing as a treatment for allergic reactions of the skin, such as those associated with hives and for the itch associated with atopic dermatitis. Vapitadine is a new selective, non-sedative H1antihistamine. In several in vitro and in vivo pharmacological models, vapitadine is at least as potent as cetirizine (Zyrtec®) and does not penetrate the blood-brain barrier. An advantage of vapitadine over other antihistamines may be the absence of the sedation, even at high doses. Vapitadine had been in phase II clinical trials for the treatment of patients with atopic dermatitis. However, no development has been reported.

Fialuridine I-124 is an isotope-labeled form of fialuridine, or 1-(2-deoxy-2-fluoro-1-D-arabinofuranosyl)-5-iodouracil (FIAU), a thymidine nucleoside analog with activity against various herpesviruses and hepatitis B virus (HBV) in vitro and in vivo. Bacterial or herpes virus thymidine kinase (TK) considered to be a target of FIAU. Fialuridine I-124 is a positron emission tomography/computed tomography (PET/CT) tracer that was developed for imaging of cells transfected with the herpes simplex virus 1 (HSV1) thymidine kinase reporter gene. This enzyme transfers a γ phosphate group fom ATP to the 5’ hydroxyl group of pyrimidine deoxynucleosides. The lipophilic tracer diffuses into the cell and is trapped in the cell with HSV1-TK activity, because the phosphorylated tracer cannot pass the plasma membrane. TK gene of bacteria was sufficiently similar to that of the viral TK of HSV1 and fialuridine I-124 could also be phosphorylated by the endogenous bacterial TK. Once phosphorylated by TK, fialuridine I-124 becomes trapped within bacteria and can be detected with positron emission tomography/computed tomography (PET/CT).