PRX-03140 is a partial agonist of the 5-HT4 receptor that is being developed by EPIX Pharmaceuticals for Alzheimer's disease. In vitro shows potent binding to 5-HT4 receptor and increased cAMP production in human embryonic kidney-293 cells expressing recombinant rat 5-HT(4) receptors. In the clinical trial, PRX-03140 was associated with a statistically significant improvement in the Alzheimer’s Disease Assessment Scale.

Arena Pharmaceuticals was developing APD-597 (JNJ-38431055), a small molecule, an orally active agonist of the G-protein coupled receptor 119 (GPR119), for the treatment of Type 2 diabetes mellitus. JNJ-38431055 was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential. In addition, extensive in vivo studies showed a more favorable metabolic profile that may avoid the generation of long-lasting metabolites with the potential to accumulate in clinical studies. In humans, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.

LY2452473 is a selective androgen receptor modulator (SARM), with potential tissue-selective androgenic/anti-androgenic activity. Upon oral administration, LY2452473 acts as an agonist in select tissues and organs, including skeletal muscle, bone and the penis, thereby binding to and activating androgen receptor (AR) while acting as an antagonist in the prostate, thereby blocking AR activation and AR-mediated cellular proliferation. This may improve muscle mass and strength, bone formation, and erectile dysfunction while not stimulating growth of the prostate. Eli Lilly was developing LY 2452473/tadalafil combination for the treatment of erectile dysfunction. In addition, Eli Lilly is studying the use of a targeted LY 2452473 therapy, as a possible improvement in quality of life for prostate cancer patients who have undergone radical prostatectomy.

GSK-1614235 (mizagliflozin) is a sodium glucose co-transporter type 1 (SGLT1) inhibitor that has been investigated for treatment in type 2 diabetes. It is thought to suppress glucose absorption from the intestine in a way that is different from conventional type 2 diabetes drugs, thereby improving postprandial hyperglycemia. Phase 1 studies have been completed.

Ezlopitant (CJ-11974) is a non-peptide neurokinin-1 receptor antagonist. Pfizer was developing ezlopitant for the potential treatment of irritable bowel syndrome and chemotherapy-induced emesis. Development of ezlopitant has been discontinued.

Dexclamol is a sedative agent. It was found to potentiate the anesthetic actions of halothane. In potentiating the effects of halothane, dexclamol behaved both qualitatively and quantitatively in a manner similar to droperidol. Dexclamol, however, was approximately 37 times less potent than droperidol in antagonizing the vasopressor effects of epinephrine. The neuroleptic agent (+)-dexclamol, but not (-)-dexclamol, affects central dopamine (DA) and norepinephrine (NE) turnover and indicates a stereochemical specificity with respect to antagonism of central DA and NE receptors. Dexclamol was as effective as droperidol at the same dose in inducing neurolepsy and in supplementing nitrous oxide anaesthesia. Changes in heart rate, respiratory rate and rectal temperature in the animals treated with dexclamol were not different from those observed in the animals treated with droperidol.

Triptolide, the active component of Tripterygium wilfordii Hook F has been used to treat autoimmune and inflammatory conditions for over two hundred years in traditional Chinese medicine. Triptolide possesses immunosuppressive, anti-inflammatory, and anti-cancer effects. Triptolide is a woody vine which is widely distributed in Eastern and Southern China. In China, triptolide is frequently used to treat autoimmune and/or inflammatory diseases due to its favorable cost–benefit ratio. Commercial preparations of triptolide have been commonly used for the treatment of inflammatory and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, nephritis and psoriasis.Triptolide has been demonstrated to exert novel chondroprotective and anti-inflammatory effects on rheumatoid arthritis. Triptolide has been used to treat ADPKD patients in clinical trials in China. Triptolide significantly protected glomerular filtration rate (eGFR) of ADPKD patients compared with placebo. Two recent small clinical studies have demonstrated tiptolide’s effectiveness against rheumatoid arthritis. A larger study confirmed the therapeutic effects of triptolide in the aforementioned studies. Triptolide is among the most powerful and broadly active antiinflammatory/immunomodulating natural products ever discovered. Triptolide acts at nanomolar concentrations and inhibits the production of various cellular targets including inflammatory cytokines, cyclooxygenase, inducible nitric oxide synthase and metalloproteinases and transcription factors. The anti-tumor activity of Triptolide in vitro and in various tumor-bearing animal models has been investigated for years, and many findings showed that Triptolide is a promising agent in anti-tumor therapy. Triptolide has been approved for Phase I clinical trials for the treatment of prostate cancer, but the anti-tumor effect and mechanism of TPL need to be further elucidated.

Sergolexole [LY 281067] is an ergoline ester similar in structure to amesergide [LY 237733], with potent and highly selective antagonist activity at serotonin 2. The preclinical pharmacologic activity of LY 281067 shows it to be a potent and highly selective serotonergic (5-HT2) receptor antagonist. Based upon binding studies with 5-HT2 receptors in brain cortical membranes and block of 5-HT-induced contractions in the rat jugular vein, LY 281067 showed high affinity at 5-HT2 receptors with a dissociation constant of approximately 1 nM. LY 281067 was a highly selective 5-HT2 receptor antagonist without appreciably binding to 5-HT1, D1 or D2 receptors or interacting with histamine (H1), cholinergic, beta adrenergic or alpha-1 adrenergic receptors in smooth muscle. LY 281067 had modest affinity at alpha-2 receptors with a dissociation constant of approximately 100 nM. Oral bioavailability of LY 281067 in spontaneously hypertensive rats was excellent with an oral to i.v. dose ratio approximating 4. Sergolexole was undergoing phase II clinical trials with Eli Lilly in the USA as a potential treatment for migraine and anxiety, but development of this compound, but development of this compound has been discontinued.

Risotilide is a Class III antiarrhythmic agent that inhibits the voltage-dependent potassium channel. Risotilide prolongs cardiac action potentials and refractory periods. It was shown to reduce ventricular vulnerability in a study on arrhythmogenic effects of left ventricular hypertrophy (LVH) in the intact heart in cats. Phase I and II trials have been conducted, but development of this drug has been discontinued.

Suricainide (also known as AHR 10718) is an aminoalkylurea derivative patented by A. H. Robins Co., Inc. as an antiarrhythmic agent. Suricainide induces a use-dependent decrease in Vmax and significantly decreased Purkinje fiber conduction velocity and action potential duration. Suricainide had no effect on slow response action potentials induced by isoproterenol but ventricular muscle action potentials were significantly prolonged by Suricainide. Suricainide significantly decreased normal automaticity, catecholamine-enhanced automaticity, and abnormal automaticity induced by barium or myocardial infarction. In preclinical modes, Suricainide suppresses the aconitine-induced canine atrial arrhythmia.