LX-1031, being developed by Lexicon Pharmaceuticals, is an oral, small-molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces 5-HT synthesis peripherally. LX-1031 is being developed for the potential treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), which is characterized by excess 5-HT. In preclinical studies, LX-1031 dose-dependently reduced expression of 5-HT in the duodenum, jejunum and ileum, but had no effect on brain 5-HT levels. It was in Phase 2 clinical trial, but later development of LX-1031 was discontinued.

PX-478 is a highly potent and selective Hypoxia-inducible Factor-1α (HIF-1α) inhibitor. It lowers HIF-1α protein levels and HIF-1 transactivation in hypoxia and in normoxia in a variety of cancer cell lines, but has a more pronounced effect on translation of proteins, such as HIF-1α in hypoxia. PX-478 also enhances the radiosensitivity of prostate carcinoma PC3 cells. Its inhibition is independent of the tumor suppressor genes VHL and p53, and may be related to derangements in glucose uptake and metabolism due to inhibition of glucose transporter-1 (Glut-1). PX-478 has excellent activity against established human tumor xenografts, inducing tumor regressions with prolonged growth delays which correlate positively with HIF-1 levels. In high-fat-diet mice, PX-478 causes reduced fibrosis and fewer inflammatory infiltrates in their adipose tissues. PX-478 had been in phase I clinical trials by for the treatment of lymphoma and solid tumors. However, this research has been discontinued.

PKI-179 is an orally efficacious dual PI3K/mTOR inhibitor, possessing antineoplastic activity. The key residues involved in binding of PKI-179 were Ala-805 in PI3Kγ and Ile-2163 in mTOR as they have lost maximum accessible surface area due to binding. By inhibiting the PI3K/mTOR signaling pathway, this agent may inhibit tumor cell proliferation and survival. Evaluation of in vivo efficacy in the nude mouse model bearing MDA-361 human breast cancer tumors showed pronounced tumor growth arrest when dosed above 10 mg/Kg.

NGX267 is a partial muscarinic receptor agonist with functionally specific M1 and M3 receptor activity, developed by Torrey Pines Therapeutics(TPTX) for the treatment of Xerostomia, Alzheimer’s disease and cognitive deficits in schizophrenia. NGX-267 had been in phase II clinical trials for the treatment of Xerostomia, however, all researchers on this drug candidate were discontinued.

Phencynonate (PHH) is a novel anticholinergic compound. It is structurally similar to scopolamine, possesses both muscarinic and nicotinic antagonistic properties as well as anti-NMDA properties. It has been developed as a safe and effective drug for the prevention of motion sickness in tablet form, it also demonstrates clear anticonvulsant effectiveness after soman poisoning in a rat model. S-isomer was more effective against motion sickness and had not anxiogenic action at therapeutic doses. S-isomer has the higher affinity and activity for mAChR in cerebral cortex and acted as a competitive mAChR antagonist. PHH was able to suppress chronic unpredictable mild stress (CUMS)-induced oxidative stress and enhance the antioxidant capacity and antioxidant proteins activity, such as superoxide dismutase 2 (SOD2) and peroxiredoxin 6 (Prdx6). PHH ameliorated CUMS-induced depressive phenotypes by up-regulating SIRT6 deacetylation activity. PHH-mediating SIRT6 pathway is required for antidepressant response and PHH can be used as a novel therapeutic to effectively treat depression. Phencynonate is in phase III clinical trials for the treatment of vertigo.

PG-116800 is a member of the hydroxyproline-based hydroxamic acid class of matrix metalloproteinase (MMP) inhibitors. PG-116800 did not modify matrix structure in osteoarthritic patients. Also, it had unexpected side effects on muscle and skeleton; it limited joint mobility, and caused arthralgia, hand oedema, palmar fibrosis, Dupuytren’s contracture and persistent tendon thickness or nodules. PG-116800 failed to reduce left ventricular remodeling or improve clinical outcomes after myocardial infarction.

Curcumol is one of the major components of the essential oil of Rhizome Curcumae with the structure of sesquiterpenoid hemiketal. It exhibits characteristics such as antitumor, ant proliferation, anti-inflammatory, anti-hepatic fibrosis, antioxidant, and antimicrobial activities with low cytotoxicity. Curcumol suppresses the Breast Cancer Cells, Colorectal Cancer Cell Line, lung adenocarcinoma cell lines and others. However, its effect and mechanisms against tumor metastasis are still unclear. Recently was discovered a preliminary mechanism the suppression of breast cancer cell metastasis by curcumol. This mechanism suggested the inhibition of MMP-9 via JNK1/2 and Akt (Ser473)-dependent NF-κB signaling pathways.

Etarfolatide (EC20) is a conjugate of folic acid and peptidic metal-chelating moiety. Technetium Tc99m radiolabeled etarfolatide is a folate-targeted molecular imaging agent that is being developed to non-invasively identify tumors that express folate receptors and that may respond to folate-targeted therapy. It is being co-developed as the companion imaging agent to Vynfinit® (vintafolide) and EC1456 (folate-tubulysin).

TMC647055 is a potent and selective nonnucleoside inhibitor of NS5B binding site 1 (NNI-1) with activity against most HCV genotypes. Binding of inhibitors to NNI-1 is purported to displace the flexible λ1 loop from its thumb domain binding site, perturbing the interaction between the NS5B polymerase finger and thumb domains and thereby locking the enzyme in an open inactive conformation. Janssen R&D Ireland (formerly Tibotec Pharmaceuticals) is developing TMC 647055 as an oral once-daily treatment for chronic hepatitis C virus infections. Phase II development is underway in Belgium, Germany and the US.