NCX-4016, a nitric oxide non-steroidal anti-inflammatory drug (NO-NSAID) which can inhibit cyclooxygenase as well as release nitric oxide, is under development by NicOx as a potential treatment for thrombosis, inflammation and rheumatoid arthritis. NCX-4016 possesses a broad spectrum of antithrombotic and antiinflammatory activities. NCX-4016 has been shown to inhibit platelet activation in vitro more effectively than aspirin, to inhibit smooth muscle cell proliferation, to exert an endothelial cell protective activity and to suppress the function of several inflammatory cells potentially involved in atherothrombosis. In animal models, NCX-4016 protected from platelet thromboembolism, prevented restenosis in atherosclerosis-prone animals, protected the heart from ischemia/reperfusion injury, and induced neoangiogenesis in critically ischemic limbs. Moreover, it displayed little or no gastric toxicity and appeared to protect stomach from noxious stimuli, including aspirin. NCX-4016 has been evaluated in healthy volunteers and found to inhibit platelet cyclo-oxygenase-1 (COX-1) similarly to or slightly less than aspirin, to raise the circulating levels of NO-degradation products, and to have little or no gastric toxicity in short term studies. NCX-4016 was in Phase II clinical trials for the treatment of vascular disorders such as peripheral vascular disease and other cardiovascular diseases including thrombosis, complications of endothelium-related diseases such as diabetes and other. But this research was discontinued.

GlaxoSmithKline was developing GSK-364735 as a human immunodeficiency virus (HIV) integrase inhibitor. The inhibition of viral DNA integration takes place by interacting at the two-metal binding site within the catalytic center of HIV integrase. GSK-364735 was successfully studied at Phase II in HIV-infected patients; however, adverse liver effects of GSK364735 were recently observed in a long-term preclinical safety study in the monkey and preclude further development of the compound.

CC-220 is a potent cereblon modulating agent that displays anti-proliferative, pro-apoptotic and immunomodulatory activity on sensitive and resistant multiple myeloma cell lines. CC-220 is currently under clinical investigation for systemic lupus erythematosus and multiple myeloma as a single agent, or in combination with dexamethasone in patients who may have previously been exposed to pomalidomide. Comparable to other Cereblon-binding agents, ex vivo treatment of CC-220 on B-cells, T-cells, and monocytes leads to the degradation of the hematopoietic transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). followed by disruption of the multiple myeloma promoting c-Myc/IRF4 axis.

GLPG-0492, an orally available selective androgen receptor modulator (SARM) was tested in a Phase I Proof of Mechanism study to assess the effect on muscle function in healthy volunteers. A biomarker effect similar to that of Oxandrolone was observed, but the data were insufficient for Galapagos to pursue GLPG-0492 further in cachexia, and further development of the compound was discontinued. GLPG-0492 is currently under development for musculo-skeletal diseases such as sarcopenia and Duchenne muscular dystrophy.

Juvantia Pharma and Orion developed ORM-12741, also known as ORM-10921, a novel selective antagonist of alpha-2C adrenoceptors for the treatment of depression and Alzheimer's disease. ORM-12741 participated in phase II clinical trial where was evaluated the safety and efficacy of the drug in patients with Alzheimer's disease. In spite of the successfully completed phase II, further study of the drug for this disease was discontinued. In addition, ORM-12741 participated in clinical trial phase II to prove the concept that this drug could prevent blood vessel spasms for Raynaud's phenomenon. Raynaud's phenomenon is a disorder of the digital blood vessels resulting in episodic impairment of blood flow. However, this study was terminated because of the recommendation by study Data and Safety Monitoring Committee to the sponsor following the interim analysis of 8 subjects.

CPI-0610 is a small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. Upon administration, the BET inhibitor CPI-0610 binds to the acetylated lysine recognition motifs on the bromodomain of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histone peptides. This disrupts chromatin remodeling and gene expression. Prevention of the expression of certain growth-promoting genes may lead to an inhibition of tumor cell growth. CPI-0610 is currently being evaluated in three Phase 1 clinical trials in the U.S.

ACT-281959 (molecular weight 850.9 g/mol), the di-ester prodrug of ACT-246475 (molecular weight 618.6 g/mol), was developed to improve absorption after oral dosing and is rapidly converted by esterases in vivo to ACT-246475 in two-steps via the formation of ACT-409100 (molecular weight 734.7 g/mol), the mono-ester prodrug. ACT-281959 is a novel potent and selective P2Y12 receptor antagonist with a wider therapeutic window. ACT-281959 showed antithrombotic efficacy after oral administration in the rat ferric chloride model. ACT-281959 entered clinical studies in healthy volunteers. ACT-281959 had been in phase I clinical trials by Actelion for the treatment of thrombosis. But there is no development reported for this study recently.

CRS-3123, also known as REP-3123, is a methionyl-tRNA synthetase inhibitor potentially for the treatment of enteric infections. CRS-3123 is in Phase 1 clinical development for the treatment of Clostridium difficile Infection (CDI). CRS-3123 is a small molecule protein synthesis inhibitor that acts on the novel target methionyl-tRNA synthetase (MetRS). REP-3123 has been shown to be active in vitro against clinical isolates of C. difficile including epidemic strains such as B1/ NAP1/027; MIC values of REP-3123 for C. difficile are typically 0.5 -- 1.0 mg/l. REP-3123 is also active against a range of clinically important aerobic Gram-positive bacteria including methicillin-susceptible and -resistant Staphylococcus aureus (MIC90 values of 0.06 and 0.25 mg/l, respectively), Streptococcus pyogenes (MIC90 0.5 mg/l) and enterococci (MIC90 32 mg/l). CRS-3123 has numerous potential advantages over current CDI therapies. In addition to being highly potent against all clinical isolates of C. difficile tested, CRS-3123 has several desirable qualities for the treatment of CDI which include: Narrow spectrum for C. difficile, which may substantially reduce the disruption of normal intestinal flora compared to current therapies; Inhibition of toxin production, potentially leading to lower morbidity and mortality; Inhibition of sporulation, potentially leading to lower rates of transmission and recurrence; A novel mechanism of action, which means that its use will not compromise the utility of systemic antibiotics while maintaining activity against pre-existing resistance mechanisms.

ADX-71149 (JNJ-40411813), a phenylpiperidine-substituted pyridone, is positive allosteric modulator (PAM) metabotropic glutamate type 2 (mGlu2) receptor activity. In fed rats, JNJ-40411813 was rapidly absorbed with an absolute oral bioavailability of 31%. ADX-71149 (JNJ-40411813) demonstrates antipsychotic activity in vivo rodents experiments. ADX-71149 (JNJ-40411813) is being jointly developed by Addex Therapeutics and Janssen Pharmaceuticals, a Johnson & Johnson company, for the treatment of epilepsy. Addex Therapeutics was also developing the candidate for schizophrenia, major depressive disorder and anxiety disorders. However, development in these indications has been discontinued.