Imeglimin is the first in class tetrahydrotriazine‐containing oral glucose-lowering agent that has been studied in clinical trials as a possible monotherapy or add-on therapy to lower fasting plasma glucose. It is being developed as an alternative and a complement to drugs that act on insulin‐resistant organs or drugs acting on insulin secretion and β‐cell protection. When investigated in preclinical studies, Imeglimin showed that it can target insulin‐resistant organs by decreasing excessive hepatic glucose production and increasing muscle glucose uptake. It also showed a potential to restore appropriate glucose‐stimulated insulin secretion and protect β‐cells from cell death under high glucose conditions. Imeglimin acts on the liver, muscle, and the pancreas (6), three key organs involved in the pathophysiology of type 2 diabetes through suspected mechanisms targeting the mitochondria and reduced oxidative stress. Imeglimin decreases hepatic glucose production and increases muscle glucose uptake. Recently, Imeglimin demonstrated increased insulin secretion in response to glucose in diabetic patients during a hyperglycemic clamp study. In clinical trials, Imeglimin treatment for 7 days raised the insulin secretory response to glucose, improved β-cell glucose sensitivity and tended to decrease hepatic insulin extraction. Imeglimin did not affect glucagon secretion.

Triciribine is a purine analogue which inhibits DNA and protein synthesis, it is a synthetic tricyclic nucleoside which acts as a specific inhibitor of the Akt signaling pathway. It selectively inhibits the phosphorylation and activation of Akt1, -2 and -3 but does not inhibit Akt kinase activity nor known upstream Akt activators such as PI 3-Kinase and PDK1. It inhibits cell growth and induces apoptosis preferentially in cells that express aberrant Akt1. In whole cells triciribine is phosphorylated by adenosine kinase which may be necessary for its activity. Triciribine is a cancer drug which was first synthesised in the 1970s and trialled clinically in the 1980s and 1990s without success. Following the discovery in the early 2000s that the drug would be effective against tumours with hyperactivated Akt, it is now again under consideration in a variety of cancers. As PTX-200, the drug is currently in two early stage clinical trials in breast cancer and ovarian cancer being conducted by the small molecule drug development company Prescient Therapeutics.

Semapimod (CNI-1493) is a cytokine inhibitor and synthetic guanylhydrazone mitogen-activated protein kinase blocker, is being developed by Cytokine PharmaSciences as a potential treatment for Crohn's disease and other inflammatory conditions. As of December 2001, a phase I study demonstrating the safety of the compound had been completed and phase II trials for psoriasis and Crohn's disease were ongoing. In April 2003, preclinical and early clinical studies were underway for a variety of indications, including congestive heart failure and pancreatitis. Semapimod inhibits activation of p38 MAPK and NF-κB and induction of cyclooxygenase-2 by TLR ligands, but not by IL-1β or stresses. Semapimod inhibits TLR4 signaling (IC50 ≈0.3 umol) and acts by desensitizing cells to LPS; it fails to block responses to LPS concentrations of ≥5 ug/ml. Semapimod had been in phase II clinical trials by Ferring Pharmaceuticals for the treatment of Crohn's disease. However, this research has been discontinued. Semapimod is in phase I clinical trials for the treatment of autoimmune disorders and inflammation.

Isoquercetin is a flavonoid, derivative of quercetin. It was isolated from various plant species including Ammothamnus Lehmanii, Caragana alaica, Cicer baldshuanicum, C. macroconthum, C. pungens, Euphorbia cyparissias, E. helioscapia, E. lathyris, E. lucida, E. purporata and others. It demonstrated radical scavenging activity, inhibitory effects on Na+/K+-ATPase and positive inotropic activity. It is protein disulfide isomerase (PDI) inhibitor. As a PDI inhibitor, this agent blocks PDI-mediated platelet activation, and fibrin generation, which prevents thrombus formation after vascular injury. Isoquercetin inhibited the replication of both influenza A and B viruses at the lowest effective concentration. Isoquercetin activates the ERK1/2-Nrf2 pathway and protects against cerebral ischemia-reperfusion injury in vivo and in vitro. It is being investigated for prevention of thromboembolism in selected cancer patients and as an anti-fatigue agent in kidney cancer patients treated with sunitinib.

Spebrutinib (CC-292, AVL-292) is a selective inhibitor of BTK that was under clinical development for the treatment of rheumatoid arthritis (phase II) and B-cell Lymphoma (phase I). The drug was discovered by Avila Therapeutics, but then acquired by Celgene. Spebrutinib covalently binds to Cys 481 in BTK, blocking the ATP-binding pocket of the enzyme. The drug is no longer in Celgene's pipeline and its development is supposed to be terminated.

Josamycin propionate, a tasteless josamycin derivative suitable for the preparation of pediatric oral suspension. After oral administration Josamycin propionate underwent metabolic transformation to Josamycin, semi-synthetic 16-membered ring macrolide, that acts via protein synthesis inhibition.

Sipatrigine (BW 619C89), a blocker of neuronal Na+ and Ca2+ channels, has neuroprotective efficacy. This drug was in phase II studies in stroke patients who received iv infusions of sipatrigine. The main adverse events observed were hallucinations and vomiting. The Phase II trial was terminated when Glaxo merged with Wellcome and a decision was made to develop the NMDA (glycine site) receptor antagonist gavestinel (from Glaxo), which showed no efficacy in a randomized, double blind, placebo- controlled trial. It was also assumed, that sipatrigine could have therapeutic potential for major depression and bipolar depression through antagonism of the two-pore-domain K+ channel TREK-1. but further evaluation of its antidepressant therapeutic and toxic effects in animal models is needed before clinical application.

Nosiheptide, an archetypal member of thiopeptide antibiotics, arises from post-translational modifications of a ribosomally synthesized precursor peptide that contains an N-terminal leader peptide (LP) sequence and a C-terminal core peptide (CP) sequence. The precursor peptide of nosiheptide (NosM) is comprised of a leader peptide with 37 amino acids and a core peptide containing 13 amino acids. Nosiheptide exhibits potent activity against multidrug-resistant Gram-positive bacterial pathogens. Nosiheptide exhibited extremely potent activity against all contemporary MRSA strains tested including multiple drug-resistant clinical isolates, with MIC values ≤ 0.25 mg l(-1). Nosiheptide was also highly active against Enterococcus spp. and the contemporary hypervirulent BI/NAP1/027 strain of Clostridium difficile but was inactive against most Gram-negative strains tested. Time-kill analysis revealed nosiheptide to be rapidly bactericidal against MRSA in a concentration- and time-dependent manner, with a nearly 2-log kill noted at 6 h at 10 × MIC. Nosiheptide also demonstrated in vivo activity in a murine model of MRSA infection, and therefore represents a promising antibiotic for the treatment of serious infections caused by contemporary strains of MRSA. Nosiheptide also has significant anti-hepatitis B virus (anti-HBV) activity in cell culture.

AstraZeneca was developing AZD-8055, an orally active mTORC1/mTORC2 inhibitor, for the treatment of advanced solid tumours. AZD-8055 is an ATP-competitive mTORC1/2 inhibitor that exhibits immunosuppressive and anticancer chemotherapeutic activities. AZD-8055 promotes antibody class switching in B cells at low doses and decreases B cell proliferation and differentiation at high doses. In vivo, this compound suppresses CC4 and CD8 T cell proliferation, increasing survival among MHC-mismatched heart transplant recipients. In vitro, AZD-8055 decreases viability of brain tumor cells; in vivo, it inhibits tumor growth. AZD-8055 had been in phase I trials by AstraZeneca for the treatment of malignant gliomas and solid tumours. However, this research has been discontinued.

Abexinostat (PCI-24781) is a novel, second-generation phenyl hydroxamic acid–based, orally bioavailable HDAC inhibitor that has previously been shown to have activity in vitro and in vivo against a broad array of cancers, including hematopoietic malignancies and bone and soft-tissue sarcomas. Abexinostat is a pan-HDAC inhibitor mostly targeting HDAC1 with Ki of 7 nM, modest potent to HDACs 2, 3, 6, and 10 and greater than 40-fold selectivity against HDAC8. Abexinostat exhibits potent antitumor activity against a variety of tumor cell lines with GI50 ranging from 0.15 uM to 3.09 uM. PCI-24781 also has an antiproliferative effect on HUVEC endothelial cells with GI50 of 0.43 uM. Abexinostat treatment causes dose-dependent accumulation of both acetylated histones and acetylated tubulin in HCT116 or DLD-1 cells, induces expression of p21, and leads to PARP cleavage and accumulation of the γH2AX. It has also shown good tolerability and activity in Phase I and II clinical trials against lymphoma, as well as against solid tumors in Phase-I trials. Additionally, it acts as a potent radiosensitizing agent and is synergistic with cytotoxic chemotherapy, such as doxorubicin in preclinical models.