Bentamapimod (AS602801) a newly developed, orally-active, ATP competitive inhibitor of JNK, which is in phase IIa clinical trials for the treatment of endometriosis. Bentamapimod showed selective cytotoxic activity against serum-cultured cancer cells and cancer stem cells in vitro. It blocks T-cell proliferation and induces apoptosis. Bentamapimod was discovered by Merck Serono. Then PregLem (a member of the Richter Group) acquired worldwide rights in 2010.

AEE-788 is an orally available anticancer agent that was being developed by Novartis. AEE-788 is a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. At the enzyme level, AEE-788 inhibited EGFR and VEGF receptor tyrosine kinases in the nm range (IC(50)s: EGFR 2 nm, ErbB2 6 nm, KDR 77 nm, and Flt-1 59 nm). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC(50)s: 11 and 220 nm, respectively). AEE-788 demonstrated antiproliferative activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor- and VEGF-stimulated human umbilical vein endothelial cells. These properties, combined with a favorable pharmacokinetic profile, were associated with a potent antitumor activity in a number of animal models of cancer, including tumors that overexpress EGFR and or ErbB2. Oral administration of AEE-788 to tumor-bearing mice resulted in high and persistent compound levels in tumor tissue. Moreover, AEE-788 efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. AEE-788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. AEE-788 had been in phase Ⅱ clinical trials by Novartis for the treatment of glioblastoma multiforme. However, this research has been discontinued.

Merimepodib has immunosuppressive activity. It targets hepatitis C indirectly through the inhibition of inositol monophosphate dehydrogenase, which exerts an acute antiproliferative effect on lymphocyte proliferation due to their almost exclusive dependence on the de novo pathway for synthesis of guanosine. Phase II clinical trial study of merimepodib for the treatment of HCV infection and psoriasis were completed. The poor pharmacokinetic-pharmacodynamic results have resulted in discontinuation of clinical trials.

Ispinesib (SB-715992) is a potent, specific and reversible inhibitor of kinesin spindle protein (KSP). KSP, also known as HsEg5, is a kinesin that plays an essential role in the formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. Ispinesib is the highly specific small-molecule inhibitor of KSP tested for the treatment of human disease. It causes mitotic arrest and growth inhibition in several human tumor cell lines and is currently being tested in multiple phase II clinical trials for treatment of the breast cancer and renal cell cancer.

Pamapimod (R-1503, Ro4402257) is a potent and selective inhibitor of p38 mitogen-activated protein kinase alpha. The preclinical data support the conclusion that pamapimod has the ability to inhibit the signs and symptoms of rheumatoid arthritis and other autoimmune diseases. Pamapimod was being developed for use in the treatment of rheumatoid arthritis. There is no clear-cut evidence that pamapimod alone or in the presence of methotrexate is efficacious in subjects with rheumatoid arthritis but it does cause adverse effects. It is unlikely that pamapimod will be useful in the treatment of rheumatoid arthritis.

Pruvanserin (EMD 281014, LY-2422347) is a selective serotonin 5-HT2A receptor antagonist. Pruvanserin was originated by Merck KGaA. Eli Lilly had been developing pruvanserin, under a global licence from Merck KGaA, for the treatment of primary insomnia and major depressive disorder. Phase II trials were completed in the US, Hungary and Spain. However, development appears to have been discontinued.

Pumosetrag is a novel, orally active and selective 5-HT 3 agonist. It is a partial agonist in rats and guinea-pig and a full agonist in the mouse, suggesting important species differences in 5-HT3 receptor structure. Pumosetrag had been in phase II clinical trials for the treatment of gastroesophageal reflux disease and irritable bowel syndrome. No serious adverse events were reported. Diarrhea was not more common on the drug and only one subject experienced pruritus. All researches on this drug candidate are discontinued.

CGP-36742 (3-Aminopropyl-n-butyl-phosphinic acid) is one of the first GABAB receptor antagonists that can penetrate the blood-brain barrier after peripheral administration. Although its affinity for GABA B binding sites labeled with a tritiated agonist is modest, being in the low micromolar range, it displays significant pharmacological activity when administered either orally or parenterally. CGP 36742 was effective in the learned helplessness paradigm in rats, dose-dependently improving the escape failures induced by the inescapable shocks, suggesting that it may have an antidepressant profile. CGP36742 displays pronounced cognition enhancing effects in Rhesus monkeys in active and passive avoidance paradigms, in an eight-arm radial maze and a Morris water maze and in a social learning task. CGP36742 blocks the late inhibitory postsynaptic potential and the paired-pulse inhibition of population spikes recorded from CA1 pyramidal neurons of the hippocampus of rats in vitro and in vivo. CGP36742 significantly enhances the release of glutamate, aspartate, glycine and somatostatin in vivo. Chronic administration of CGP36742 causes an up-regulation of GABA(B) receptors in the frontal cortex of rats. The effects of CGP36742 on cognition were investigated in a double-blind, placebo-controlled study undertaken as the first assessment of the efficacy of CGP36742 in 110 patients age 59–85 years with Mild cognitive impairment. The results showed significant improvement in working memory, psychomotor speed and attention with SGS742 as compared with placebo. SGS742 appeared to be safe and well tolerated in this study.

Sitamaquine (WR-6026) is an orally active 8-aminoquinoline analog in development by the Walter Reed Army Institute, in collaboration with GlaxoSmithKline (formerly SmithKline Beecham), for the potential treatment of visceral leishmaniasis. Phase III trials for the treatment of visceral leishmaniasis had been initiated by March 2002, at which time GlaxoSmithKline hoped to file an MAA in 2003. By 1999, the compound had also undergone phase I trials in HIV-infected individuals for the treatment of Pneumocystis carinii infection. Preclinical studies have been conducted in primates and rodents for the potential treatment of Babesia microti infection.

Ragaglitazar (DRF 2725, NNC 61-0029) is phenoxazine analog of phenyl propanoic acid having dual (PPARα and PPARγ) agonist property intended to restore insulin sensitivity and correct diabetic dyslipidemia. PPAR-α is highly expressed in liver and muscle and upon activation leads to decreases in plasma triglycerides and increases in HDL cholesterol levels. PPAR-γ activation leads to enhancement of glucose uptake in skeletal muscles and adipose tissue. Ragaglitazar provided the glycemic control that was comparable with that of pioglitazone and, compared with placebo, provided a significant improvement in the lipid profile.