Denagliptin is a dipeptidyl peptidase IV (DPP-IV) and and tripeptidyl-peptidase inhibitor, which entered phase III clinical trials in 2006 for the treatment of type 2 diabetes mellitus at GlaxoSmithKline. Development of this compound was put on hold due to unfavorable preliminary data from preclinical long-term toxicity trials. Stress testing or forced degradation studies of denagliptin revealed that drug was stable in the solid-state, but degraded in solution, in blends with all excipients, and in capsules predominantly by cyclization to (3S,7S,8aS) amidine, which epimerized to (3S,7S,8aR) amidine.

Tiomolibdic acid salt, Bis-choline tetrathiomolybdate (ATN-224, WTX-101), is under investigation as a therapy against different cancers and Wilson’s disease (WD). ATN-224 is a second-generation analog of ammonium tetrathiomolybdate. ATN-224 is a novel copper chelator. ATN-224 inhibits CuZn superoxide dismutase 1 (SOD1) leading to antiangiogenic and antitumor effects. Strategically tailoring combination regimens that include ATN-224 and target ROS may be a viable approach to advance the treatment of melanoma. ATN-224 is in phase III clinical trial for the treatment of Hepatolenticular degeneration. WTX-101 is in phase II clinical trials for the treatment of Wilson's disease. Once daily WTX-101 treatment over 24 weeks improved neurologic disease, hepatic status and copper control in newly diagnosed WD patients. WTX-101 appears well tolerated. Drug-induced, paradoxical, neurological deterioration was not observed. This compound has received orphan drug designation in both the United States and the European Union. WTX-101 was originally discovered by University of Michigan and now is being developed by Wilson Therapeutics by acquisition.

Crenolanib is an orally active, highly selective, small molecule, next generation inhibitor of platelet-derived growth factor receptor (PDGFR) tyrosine kinase. Crenolanib, manufactured by Arog Pharmaceuticals in Dallas, is taken orally with chemotherapy. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable, selective small molecule inhibitor of type III tyrosine kinases with nanomolar potencies against platelet-derived growth factor receptors (PDGFR) (isoforms PDGFRα and PDGFRβ) and Fms-related tyrosine kinase 3 (FLT3). Besides PDGFR and FLT3, crenolanib does not inhibit any other known receptor tyrosine kinase (RTK) (e.g. VEGFR and FGFR) or any other serine/threonine kinase (e.g., Abl, Raf) at clinically achievable concentrations. Preclinical trials have shown Crenolanib to be active in inhibiting both wild-type and mutant FLT3. Crenolanib is cytotoxic to the FLT3/ITD-expressing leukemia cell lines Molm14 and MV411, with IC50s of 7 nM and 8 nM, respectively. In immunoblots, crenolanib inhibited phosphorylation of both the wild-type FLT3 receptor (in SEMK2 cells) and the FLT3/ITD receptor (in Molm14 cells) in culture medium with IC50s of 1-3 nM. Importantly, the IC50 of crenolanib against the D835Y mutated form of FLT3 was 8.8 nM in culture medium. Furthermore, crenolanib had cytotoxic activity against primary samples that were obtained from patients who had developed D835 mutations while receiving FLT3 TKIs. In vitro, the IC50 of crenolanib for inhibition of FLT3/ITD in plasma was found to be 34 nM, indicating a relatively low degree of plasma protein binding. From pharmacokinetic studies of crenolanib in solid tumor patients, steady state trough plasma levels of roughly 500 nM were found to be safe and tolerable, suggesting that crenolanib could potentially inhibit the target in vivo. Crenolanib has no significant activity against c-KIT, which may be an advantage in that myelosuppression can be avoided.1Furthermore, there was no evidence of QTc prolongation in patients treated with crenolanib. In summary, crenolanib offers a number of advantages over other FLT3 TKIs. Clinical trials of crenolanib in AML patients with FLT3 activating mutations are being planned.

CGC-11047 is a polyamine analog designed to halt cell growth and induce apoptosis of cancer cells. In preclinical models CGC-11047 significantly inhibited tumor development in both lung and prostate cancer models when administered as a single agent. In the lung cancer model, CGC-11047 potentiated the antitumor effect of cisplatin. Although potent activity was observed with CGC-11047 and bevacizumab when administered as single agents in the prostate cancer model, the combination arm significantly enhanced antitumor activity compared with either agent alone. In all experiments, CGC-11047 was well tolerated with no adverse effects on bodyweight gain.

Diproteverine is a calcium channel blocking agent. Diproteverine provoked a dose-dependent inhibition of LHRH-stimulated luteinizing hormone release. Diproteverine does not modify mean blood pressure. Diproteverine administered with and without pharmacologic autonomic blockade in the conscious dog causes dose-related depressant effects on sinus node function and atrioventricular conduction without producing significant vasodilatation. Diproteverine caused a redistribution of the available coronary blood flow, to the benefit of an ischemic area of the myocardium. The combination of the reduction in heart rate, to lower cardiac oxygen demand, with the beneficial action on coronary blood flow should result in diproteverinebeing particularly beneficial for the treatment of angina pectoris.

Talaglumetad (also known as LY-544344) is a bicyclohexane derivative patented by Eli Lilly and Company as modulators of metabotropic glutamate receptor. Talaglumetad acts as a prodrug of Eglumegad, a selective agonist of metabotropic glutamate receptors (mGluR2/3) and metabolized to release active compound by both human jejunal homogenates and rat liver homogenates. In experiments on mice, Talaglumetad was found to be as effective as diazepam for treating anxiety symptoms in several standard tests, but without producing any of the negative side effects of diazepam such as sedation and memory impairment.

CS-834 is a beta-lactam antibiotic of a carbapenem class, developed by the Japanese company Sankyo Co. Ltd. CS-834 is an ester-type prodrug of the active metabolite R-95867. The drug showed potent and well balanced antibacterial activity as well as stability against dehydropeptidase-I. The in vivo efficacy of CS-834 was evaluated in murine systemic infections caused by 16 strains of gram-positive and -negative pathogens. The efficacy of CS-834 was in many cases superior to those of cefteram pivoxil, cefpodoxime proxetil, cefdinir, and cefditoren pivoxil, especially against infections caused by S. aureus, penicillin-resistant S. pneumoniae, E. coli, Citrobacter freundii, and Proteus vulgaris. Pharmacokinetics of CS-834 was evaluated in healthy male volunteers, but no further clinical development of the drug was reported.

Halopenium was studied as an antibacterial and antifungal agent.

Prizidilol (also known as SKF 92657) is arylpyridazinylhydrazine derivative patented by Smith Kline and French Laboratories Ltd. as an antihypertensive agent. In clinical trials, Supine and standing blood pressure measured 24--27 h after drug intake was reduced Slight but significant decreases in heart rate were seen after moderate doses of prizidilol. A more pronounced blood pressure reduction was noticed 2--7 h after drug administration. Prizidilol was well tolerated, although dizziness and tiredness were reported by four patients and edema by two.

Pelanserin is an antagonist of the serotonin 5-HT2 receptor and blocks alpha 1-adrenoceptor. Experiments on dogs have revealed that pelanserin showed adequate pharmacokinetic and pharmacodynamics profiles as an antihypertensive agent that is why the drug possessed potential therapeutic usefulness in the treatment of hypertension. Pelanserin was undergoing phase II clinical trials by Cinvestav in Mexico; however, these studied were discontinued.