Vicriviroc or SCH 417690 is a potent and selective antagonist of the CCR5 receptor. vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5'-[35S]triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represented a promising new candidate for the treatment of HIV-1 infection. Vicriviroc for HIV treatment was previously in Phase III studies but has since been discontinued.

Fosbretabulin (Combretastatin A4 phosphate, CA4P) is the lead compound of a relatively new class of agents termed vascular disrupting agents that target existing tumor blood vessels. Rapid tumor blood flow shutdown has been demonstrated in preclinical models and patients by various techniques such as dynamic contrast-enhanced MRI, perfusion computed tomography and PET scans following CA4P infusion. CA4P typically induces rapid tumor necrosis in the center of the tumor and leaves a rim of viable cells in the periphery. In oncology, CA4P does not appear to be that active by itself, but may be more efficacious when combined with chemotherapy, antiangiogenic therapy and radiation therapy. Combretastatin was initially isolated from the root bark of the South African Bush willow Combretum caffrum in 1982 by Pettit and colleagues at the Arizona State University (AZ, USA). Combretastatin A4 phosphate binds avidly to tubulin at the colchicine-binding site to inhibit microtubule assembly and destabilize the cytoskeleton. CA4P is a tubulin-binding agent that binds at or near the colchicine binding site of β-tubulin (Kd = 0.40 uM), inhibits tubulin assembly with IC50 of 2.4 uM. Fosbretabulin has orphan drug status in the EU and the US for the treatment of ATC (Anaplastic Thyroid Cancer). Later the development of this drug was discontinued.

Omigapil (CGP 3466 or TCH346) is a structurally related analog of R-(-)-deprenyl that exhibits virtually no monoamine oxidase type B inhibiting activity but is neuroprotective in the picomolar concentration range. It binds to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and at subnanomolar concentrations prevent the S-nitrosylation of GAPDH, inhibit GAPDH-Siah binding and prevent the nuclear translocation of GAPDH. Omigapil demonstrated promising potential in the treatment of Parkinson's disease and motoneuron disease in animal models, however, it did not show efficacy in clinical trials. Omigapil is in development for the treatment of congenital muscular dystrophy.

Talsaclidine (WAL-2014) is a selective full agonist of M1 muscarinic receptor, having partial agonist activity on the M2 and M3 subtypes (with no in vivo consequences). The general receptor profile of talsaclidine demonstrates a nearly specific interaction with muscarinic receptors, having only weak binding affinity for alpha1- and nicotinic receptors. The drug is being tested in phase III of clinical trials for the treatment of Alzheimer's disease.

Ruboxistaurin is an orally bioavailable, selective, potent inhibitor of protein kinase C β developed for treating diabetic retinopathy. In vitro and in vivo non-clinical models have demonstrated that Ruboxistaurin decreases PKC β activity and ameliorates many of the effects of PKC β on pathologic processes in the retina. Ruboxistaurin prevents the slowing of retinal blood flow that is observed by fluorescein video angiography in the eyes of diabetic rats. It is also reported to cause regression of retinal neovascularization produced by laser-induced major branch vein occlusions in a porcine model. Ruboxistaurin positively affected the diabetes-induced retinal blood flow abnormalities in a Phase Ib study in diabetic patients. Ruboxistaurin is in phase III clinical trials for the treatment of diabetic nephropathy and diabetic macular edema. Eli Lilly had submitted Ruboxistaurin for approval in the US and the EU; however, the company subsequently discontinued development as it was unable to demonstrate sufficient efficacy

Acolbifene, the active metabolite of EM-800, was identified as a pure antagonist that acts on both activation domains of the ERs. It is in Phase III clinical trials for the prevention of breast cancer and vasomotor symptoms (Hot flush) in postmenopausal women. Most commonly reported adverse events included irregular menses, leg/muscle cramps, diarrhea, and hot flashes. No serious adverse events were reported.

Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. Enzastaurin (LY317615) is a potent PKCβ selective inhibitor. Enzastaurin suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis. Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. Eli Lilly discontinued development of enzastaurin after top-line data from the double-blind, international Phase III PRELUDE trial in 758 DLBCL patients showed that enzastaurin missed the primary endpoint of improving DFS vs. placebo.

Amibegron (SR 58611A or SR 58611) is a highly selective agonist for atypical beta3-adrenoceptors. It stimulates neuronal activity in a specific area of the prefrontal cortex and also inhibits intestinal motility. Amibegron was in phase III trials worldwide for the treatment of depression and generalised anxiety disorder but development of the product was discontinued in 2008. Amibegron has been tested for its potential as a treatment for irritable bowel syndrome.

Zosuquidar (LY-335979) is an experimental antineoplastic drug. It is is a potent modulator of P-glycoprotein-mediated multi-drug resistance with Ki of 60 nM. Zosuqidar was initially characterized by Syntex Corporation, which was acquired by Roche in 1990. Roche licensed the drug to Eli Lilly in 1997. It was granted orphan drug status by the FDA in 2006 for AML. Zosuquidar Trihydrochloride had been in phase III clinical trials by Kanisa Pharmaceuticals for the treatment of acute myeloid leukaemia. However, this research has been discontinued.

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.