Valspodar (PSC-833) is a derivative of cyclosporin but devoid of the immunosuppressive and nephrotoxic properties seen in cyclosporin A. It exhibited high-affinity binding to Mdr1 P-glycoprotein (P-gp) and demonstrated multidrug resistance-reversing activity superior to cyclosporin A and verapamil both in vitro and in vivo. Preclinical and phase I/II clinical data have indicated that plasma levels of PSC-833 with multidrug resistance-reversing activities are achievable. Potent inhibition of intestinal, hepatobiliary and blood-brain barrier P-gp function has been demonstrated. The toxicity profiles of valspodar are acceptable and dose-limited by transient and reversible cerebellar ataxia. It has shown multidrug resistance-modulating activities towards acute myeloid leukemia, multiple myeloma and ovarian cancer in phase I/II clinical trials. However, the company discontinued development of valspodar in April 2001 following disappointing results reported from several multicentre phase III studies.

Firategrast (SB683699) is an orally bioavailable alpha4 beta1/alpha4 beta7 integrin antagonist designed to reduce trafficking of lymphocytes into the central nervous system (CNS), that had been studied in phase II trials at GlaxoSmithKline under a license from Mitsubishi Tanabe Pharma for the oral treatment of multiple sclerosis (MS) in Europe. GlaxoSmithKline and Tanabe Seiyaku (now Mitsubishi Tanabe Pharma) had been studying the drug candidate for the treatment of asthma, rheumatoid arthritis (RA) and Crohn’s disease, but these studies had being discontinued. Firategrast is a drug for the treatment of multiple sclerosis (MS) which is found to be caused by the migration of leucocytes (such as monocytes, T cells, B cells and dendritic cells) into CNS. And the integrin α4β1 is found to take participate in the migration through activating the leucocytes. Firategrast has a much shorter half-life than natalizumab with about 2.5 hours to 4.5 hours. It is found to inhibit the binding of the integrins to the associated ligands, including vascular cell adhesion protein 1 and mucosal addressin cell adhesion molecule 1. In CNS, firategrast treatment caused moderate decreases of total lymphocyte count, lymphocyte subset count and the ratio of CD4 to CD8. In peripheral blood, firategrast treatment resulted in the increases of total lymphocyte count, all lymphocyte subset count as well as the peripheral CD34+ early haematopoietic progenitor cell count. Firategrast was well tolerated at the maximum doses of 1200 mg for men and 900 mg for women. Firategrast showed no side effects, such as PML or JC-virus reactivation, at these doses. In Phase I clinical trials, the administration of firategrast significantly reduced the cumulative number of new gadolinium-enhancing lesions in patients with relapsing remitting MS.

Levemopamil is a novel compound of the phenylalkylamine class of calcium channel blockers, possesses exceptionally high blood-brain barrier penetrability characteristics. It has a potent antagonistic action on serotonin 5-HT2-receptors. Activation of these receptors stimulates inositol phospholipid hydrolysis that can lead to the release of Ca2+ from intracellular stores as well as protein kinase C activation. Levemopamil thus has the potential for blocking deleterious increases of intracellular calcium arising from both intracellular stores and from the extracellular space. Levemopamil reduce both infarct size and extent of neuronal injury following permanent focal or transient global ischemia. The acute effect of bilateral clamping of carotid arteries on local cerebral blood flow was measured in the presence and absence of levemopamil in a separate group of rats. The data suggest that pretreatment with levemopamil reduces impairment in spatial behaviour and that this effect seems not related to the compound's cerebral vasodilatory action, but to direct neuronal mechanisms.

AE-37 (ANAVEX2-73, Tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanemethanamine) is an orally available drug candidate developed to potentially modify Alzheimer’s disease rather than temporarily address its symptoms. It has a clean Phase 1 data profile and shows a reversal of memory loss (anti-amnesic properties) and neuroprotection in several models of Alzheimer’s disease. This drug is in Phase II trials for Alzheimer's disease, phase I trials for epilepsy, and in preclinical trials for amyotrophic lateral sclerosis, Parkinson's disease, Rett syndrome, stroke. AE-37 may function as a pro-drug for ANAVEX19-144 and acts as a muscarinic receptor and a moderate sigma1 receptor agonist.

Sumanirole is a novel dopamine agonist with high affinity and efficacy at D2 dopamine receptors and has a substantial degree of selectivity for the D2 receptor over other dopamine receptor subtypes. It had been in clinical trials for the treatment of Parkinson’s disease and restless leg syndrome but these studies were terminated for the efficacy reason.

Ebiratide (Hoe 427) is a peptide analog of corticotrophin (ACTH 4-9). Ebiratide is endocrinologically inert. Ebiratide is highly lipophilic and has prolonged metabolic stability. Ebiratide exerts neurotrophic properties in vivo. It also was proven to have significant effects on acetylcholine metabolism. It has been investigated in the treatment of Alzheimer's disease.

Luteolin, 3',4',5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Luteolin possesses a variety of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial and anticancer activities. Numerous studies have shown that luteolin possesses beneficial neuroprotective effects both in vitro and in vivo.

Ranirestat (AS-3201, SX-3030, SX-3202) is an oral aldose reductase inhibitor. (-)-enantiomer (AS-3201) is 10 times more potent in inhibition of the aldose reductase and 500 times more potent in the in vivo activity than the corresponding (+)-enantiomer (SX-3202). Ranirestat is being developed by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) for the treatment of diabetic complications, primarily diabetic neuropathy. Ranirestat is a well-tolerated front-line inhibitor. It reproducibly exhibits some degree of measurable objective beneficial outcomes in diabetic neuropathy.

Ibutamoren (L-163,191 MK-0677) is a spiropiperidine agonist of the ghrelin receptor and a growth hormone secretagogue. Ibutamoren mimics the actions of growth hormone releasing peptide-6 to increase serum levels of serum insulin-like growth factor-I (IGF-I). Orally active Ibutamoren was being developed by Merck & Co. for a variety of indications, including fibromyalgia, muscle wasting/weakness in patients with chronic kidney disease, Alzheimer's disease and fractures.However, there has been no recent development reported or development has been discontinued for these indications.

Phenserine, a derivative of physostigmine, was first described as an inhibitor of acetylcholinesterase (AChE) and was shown to improve cognition in various experimental paradigms in rodents and dogs. It was clinically tested for Alzheimer's disease, with moderate success in initial Phase II studies. Phenserine is also unique because of differing actions of its enantiomers: (-)-phenserine is the active enantiomer for inhibition of AChE, whereas ( )-phenserine (Posiphen®) has weak activity as an AChE inhibitor and can be dosed much higher. Posiphen® is a small, hydrophobic, orally available molecule that enters the brain readily. It is the only drug ever described that inhibits more than one neurotoxic aggregating protein. Posiphen® inhibits synthesis of amyloid precursor protein (APP), tau and α-Synuclein. mRNA translation of neurotoxic aggregating proteins is up-regulated by iron (Fe) and down-regulated by iron regulatory protein-1 (IRP1). Posiphen® interferes with this second step of the common cascade of the aggregating proteins. It enhances the binding and/or activity of IRP1 to the iron response element (IRE) stem loop in the 5’UTR of the mRNAs of neurotoxic aggregating proteins, therefore specifically lowering their synthesis. By potentiating the IRE/IRP1 complex, Posiphen® lowers the level of free mRNA to be translated by the ribosome. Posiphen® is in development for the treatment neurodegenerative diseases.