Filibuvir (PF-868554), being developed by Pfizer, is an orally administered, non-nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase for the potential treatment of chronic hepatitis C (HCV) infection. Filibuvir is a potent and specific inhibitor of the virally encoded NS5B polymerase, and inhibited genotype 1 sub genomic HCV replication in the cell-based replicon system. In phase I and a IIa clinical trial in treatment-naïve patients infected with genotype 1 HCV, filibuvir monotherapy or in combination with pegylated IFNα2a/ribavirin (the standard of care [SoC] for HCV infection) for up to 4 weeks significantly reduced HCV RNA levels compared with placebo or SoC alone. However, company stopped development of the drug and the decision to halt development of the non-nucleoside polymerase inhibitor, which was in mid-stage testing, was not related to any safety issues.

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.

GSK-923295 is a small-molecule inhibitor of the mitotic kinesin centromere-associated protein E (CENP-E), and the third novel drug candidate to arise from Cytokinetics' broad strategic alliance with GlaxoSmithKline (GSK). GSK-923295 demonstrated a broad spectrum of activity against a range of human tumor xenografts grown in nude mice, including models of colon, breast, ovarian, lung and other tumors. GSK-923295 is the first drug candidate to enter human clinical trials that specifically targets CENP-E and is currently in Phase I human clinical trials being conducted by GSK. GSK-923295 inhibited release of inorganic phosphate and stabilized CENP-E motor domain interaction with microtubules. Inhibition of CENP-E motor activity in cultured cells and tumor xenografts caused failure of metaphase chromosome alignment and induced mitotic arrest, indicating that tight binding of CENP-E to microtubules is insufficient to satisfy the mitotic checkpoint. Consistent with genetic studies in mice suggesting that decreased CENP-E function can have a tumor-suppressive effect, inhibition of CENP-E induced tumor cell apoptosis and tumor regression.

Lirimilast is representative of a new structural class of PDE4 inhibitors, the benzofurans. It it is highly selective type 4 cyclic nucleotide phosphodiesterase inhibitor. Lirimilast inhibited human inflammatory cell functions that previously were reported to be sensitive to PDE4 inhibitors. It showed some selectivity for neutrophil and eosinophil functions over those of monocytes and T lymphocytes when compared to cilomilast and other reference PDE4 inhibitors. Lirimilast exhibited a broad profile of anti-inflammatory activity in animal models of COPD and asthma. Lirimilast produced emesis in primates. 1 week of treatment with the selective PDE4 inhibitor lirimilast does not affect FEV1 and sputum cell numbers in patients with asthma or chronic obstructive pulmonary disease (COPD). However, such treatment does seem to reduce levels of albumin and eosinophil cationic protein in sputum samples obtained from patients with COPD.

Daniquidone, also known as Batracylin, is a water-insoluble heterocyclic amide with potential antineoplastic activity. Daniquidone inhibits topoisomerases I and II, thereby inhibiting DNA replication and repair, and RNA and protein synthesis. Batracylin advanced as an anticancer agent to Phase I clinical trials where dose limiting hemorrhagic cystitis (bladder inflammation and bleeding) was observed.

Lubazodone (YM 992) or (S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride, exhibited the biochemical profile of a selective serotonin (5-HT) reuptake inhibitor (SSRI) with 5-HT2A receptor antagonistic activity. It has been studied in the treatment of depression.

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.

Pirlindole is a selective and reversible inhibitor of monoamine oxidase (MAO) subtype A (MAO-A). It exerts an inhibitory effect on noradrenaline and 5-hydroxytryptamine reuptakes. It has no effect on the dopaminergic and cholinergic systems. It has only a low potential for amplifying tyramine and noradrenaline pressor effect, which makes one expect that it will not be at the basis of a ‘cheese effect’. Pirlindole was approved in some European and non-European countries for the treatment of depression. The antidepressant efficacy and safety of pirlindole have been demonstrated in a number of placebo- and active comparator-controlled studies and are supported by many years of clinical experience in the treatment of depression. The drug's efficacy and safety have also been demonstrated in the treatment of fibromyalgia syndrome. Pirlindole has a favorable tolerability profile, with no deleterious effect on cardiovascular dynamics. The effect of pirlindole on sensorimotor performance relevant to driving a motor vehicle is similar to that of placebo, as pirlindole appears to have an activating rather than a sedating antidepressant profile. Pirlindole prevented qualitative alteration (transformation) in the catalytic activity of membrane-bound type A monoamine oxidases (MAO-A), pathogenetically important for the development of the audiogenic seizures.

Tagorizine (also known as AL-3264) is a pyridylacrylamidoalkylpiperazine derivative patented by Dainippon Pharmaceutical Co., Ltd as an antiallergic agent. Tagorizine acts as 5-lipoxygenase inhibitor and blocks histamine H1-receptors in isolated guinea pig trachea, inhibits antigen-induced histamine release from isolated rat peritoneal mast cells, and suppress leukotriene production from activated human leukocytes. In preclinical models Tagorizine inhibited the antigen-induced leukotriene production in the abdominal cavity of passively sensitized rats and suppressed the arachidonic acid-induced ear edema in mice.

Amitivir [LY217896], an amino thiadiazole derivative, is an inhibitor of the enzyme inosine monophosphate dehydrogenase. Amitivir has activity against several influenza A and B viruses. Amitivir possesses broad antiviral activity in vitro and in animal models against or thomyxo-and paramyxoviruses. In phase I studies with healthy volunteers, single doses of up to 500 mg were well tolerated and had predictable pharmacokinetics. Oral LY217896 was in trial for prevention of experimental influenza A virus infection and illness in humans. LY217896 was associated with asymptomatic rises in serum uric acid levels and was ineffective in modifying the virologic or clinical course of experimental influenza A (H1N1) virus infection. Amitivir development was discontinued.