NPV-LEQ506 is an orally bioavailable small-molecule Smoothened (Smo) antagonist with potential antineoplastic activity. NPV-LEQ506 selectively binds to the Hedgehog (Hh)-ligand cell surface receptor Smo, which may result in the suppression of the Hh signaling pathway, thereby inhibiting tumor cell growth. NPV-LEQ506 is a second-generation inhibitor of smoothened (Smo) with IC50s of 2 and 4 nM in human and mouse, respectively. NPV-LEQ506 has been in clinical trials with Novartis studying the treatment of advanced solid tumors, recurrent or refractory medulloblastoma, and locally advanced or metastatic basal cell carcinoma.

Bristol-Myers Squibb developed BMS-641988 as a nonsteroidal androgen receptor antagonist for the treatment of prostate cancer. BMS-641988 participated in phase I clinical trials in patients with castration-resistant prostate cancer in Japan and in the USA. However, further information is not available.

BMS 777607 is a substituted 2-aminopyridine shown to inhibit the RON and cMet receptor tyrosine kinases, for the treatment of solid tumors. BMS 777607 demonstrated ligand stimulated and constitutive Met phosphorylation, and inhibition of tumor cell proliferation, in preclinical studies. Preclinical data indicated that BMS 777607 inhibited RON, blocking the conversion of micrometastases to overt metastases by boosting antitumor immunity. Bristol-Myers Squibb conducted a phase I/II trial of BMS 777607 for the treatment of advanced solid tumors in Australia. As at December 2016, no recent reports of development had been identified for preclinical development in Cancer in the USA.

Scyllo-inositol (ELND005) is an inositol isoform. Inositol is a derivative of cyclohexane with six hydroxyl groups, making it a polyol. It also is known as a sugar alcohol, having exactly the same molecular formula as glucose or other hexoses. Scyllo-inositol (ELND005) is a naturally occurring plant sugar alcohol found most abundantly in the coconut palm. It appears to accumulate in a number of human tissues and biofluids through dietary consumption. It has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. Although scyllo-inositol (ELND005) at pharmacologic doses may alter myo-inositol levels and indirectly affect phosphatidyl-inositol signaling, its main effects are thought to be binding and inhibition of beta-amyloid 42 peptide aggregation and formation of beta-amyloid fibrils. In transgenic animals, scyllo-inositol (ELND005) reduced brain beta-amyloid concentrations and plaque burden, preserved synaptic density, and improved learning deficits. Scyllo-inositol (ELND005) also appears to neutralize toxic effects of beta-amyloid oligomers, including amelioration of oligomer-induced synaptic loss, long-term potentiation inhibition, and memory deficits. Scyllo-inositol (ELND005) is an attractive candidate as a potential disease-modifying oral treatment for Alzheimer disease.

GlaxoSmithKline is developing GSK-356278 as a selective, brain-penetrant phosphodiesterase 4 (PDE4) inhibitor that demonstrates anxiolytic and cognition-enhancing effects. Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. The drug was studied for the treatment of Huntington's disease, depressive and anxiety disorders. GSK-356278 has completed phase I clinical trials for evaluation of the safety, tolerability, and pharmacokinetics in male volunteers with the therapeutic dose for future clinical development.

IOWH032 is a synthetic extracellular CFTR inhibitor, originally developed to treat diarrhea, that entered Phase II clinical trials in 2013 but did not progress further in clinical development. iOWH032 has low CFTR inhibition potency (IC50 > 5 uM) and hence rapid (seconds or less) dissociation from CFTR. iOWH032 inhibited secretion by nearly 70% as measured on a semi-quantitative fecal output scale.

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.

Resolvin E1 (RvE1 or RX-10001) is a trihydroxy eicosapentaenoic acid metabolite that has a role as an anti-inflammatory agent and a human xenobiotic metabolite. This compound binds to leukotriene B4 (BLT-1) on neutrophils and to ERV-1/ChemR23 on monocyte/macrophages. Resolvin E1 has been shown to reverse experimental periodontitis and dysbiosis in rats. Furthermore, in a murine model of Alzheimer’s disease, Resolvin E1 (in combination with lipoxin A4) decreased neuroinflammation. Resolvin E1 was also suggested as a potential therapeutic target for psoriasis. A phase I clinical trial to test drug safety in healthy volunteers has been completed in 2009.

Gemilukast (ONO-6950) is an orally active compound that has been evaluated for the treatment of asthma. It is an CysLT1 and CysLT2 antagonist. Activation of CysLT2 receptors has been suggested to contribute to antigen-induced bronchoconstriction (constriction of the airways in the lungs) in certain asthma patients. In addition to its CysLT1 and CysLT2 antagonist activity, Gemilukast was shown to dose-dependently reduce LTC4-induced bronchoconstriction in asthmatic models, and reduce antigen-induced constriction of isolated human bronchi. A phase II trial with Gemilukast was discontinued in 2018.