TD 8954 (also known as TAK 954) is a selective serotonin 5-HT(4) receptor agonist. It is known a potential role for potent and efficacious 5-HT(4) receptor agonists in the treatment of Alzheimer's disease (AD). TD 8954 participated in phase I clinical trials to study its potential role in the treatment of AD. However, this study was discontinued. In addition, TD 8954 is involved in phase II clinical trials to investigate its effect on gastrointestinal and colonic transit in diabetic or idiopathic gastroparesis participants and for the prophylaxis and treatment of postoperative gastrointestinal dysfunction in participants undergoing large- and small-bowel resection.

PAK4-IN-1 (KPT-9274) is a first-in-class, orally bioavailable, small molecule immunometabolic modulator that works through non-competitive dual inhibition of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). Co-inhibition of these targets is believed to lead to synergistic anti-tumor effects through suppression of ß-catenin by blocking PAK4, leading to both immune cell activation and inhibition of tumor growth, energy depletion through NAMPT inhibition, blockade of DNA repair, cell cycle arrest and ultimately apoptosis. KPT-9274 may therefore have both immune-activating and direct antitumor effects. In contrast, normal cells are less sensitive to inhibition by KPT-9274 due in part to their relative genomic stability and lower metabolic demands. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. Oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy. KPT-9274 is being evaluated in a phase I human clinical trial in solid tumors and lymphomas, which will allow this data to be rapidly translated into the clinic for the treatment of RCC.

Otenabant (CP-945,598) is Pfizer developed as a potent and selective cannabinoid receptor CB1 antagonist with Ki of 0.7 nM, which exhibits 10,000-fold greater selectivity against human CB2 receptor, for treatment of obesity. In clinical trial III Pfizer decided to discontinue the development program based on changing regulatory perspectives on the risk/benefit profile of the CB1 class and likely new regulatory requirements for approval.

Rafigrelide is an imidazoquinazoline derivative patented by pharmaceutical company Shire LLC as platelet-lowering agent for the treatment of myeloproliferative diseases. Rafigrelide is a chemical analog of anagrelide, which is used to reduce platelet counts in myeloproliferative disorders. Compared with anagrelide, Rafigrelide has reduced potency against phosphodiesterase III, which may help to reduce potential side effects. The concentration of Rafigrelide that produces 50% of the maximum inhibition (IC50) of PDE III is 164 nM, making it an approximately 200-fold less potent inhibitor of phosphodiesterase III than 3-hydroxy anagrelide. In the clinical trial, Rafigrelide showed antithrombotic properties during a two-week treatment period in healthy male volunteers. The reductions in thrombus formation were seen in surrogate models of both high and low shear rates suggesting drug efficacy in different arterial conditions.