TAK-063 is a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor with IC50 of 0.30 nM; >15000-fold selectivity over other PDEs. TAK-063 is currently being evaluated in clinical trials for the treatment of schizophrenia. Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP phosphodiesterase highly expressed in medium spiny neurons (MSNs) in the striatum. TAK-063 represents a promising drug for the treatment of schizophrenia with potential for superior safety and tolerability profiles.

SB-203580 was originally prepared as inflammatory cytokine synthesis inhibitor that subsequently was found to be selective inhibitor of p38 MAP kinase. SB-203580 is a p38 MAPK inhibitor with IC50 of 0.3-0.5 uM in THP-1 cells, 10-fold less sensitive to SAPK3(106T) and SAPK4(106T) and blocks PKB phosphorylation with IC50 of 3-5 uM. SB203580 induces autophagy in human hepatocellular carcinoma (HCC) cells. Development of SB-203580 for cancer; postmenopausal osteoporosis; rheumatoid arthritis; septic shock has been discontinued.

Carnosol is an ortho-diphenolic diterpene with an abietane carbon skeleton with hydroxyl groups at positions C-11 and C-12 and a lactone moiety across the B ring. Carnosol is the product of oxidative degradation of carnosic acid. Carnosol is a naturally occurring phytopolyphenol found in rosemary that functions as an antioxidant, antimicrobial, and anticarcinogen. Carnosol has been shown to inhibit inductions of COX-2 by blocking PKC signaling. Carnosol is an inhibitor of AR and ER α. Several pre-clinical studies have suggested that carnosol selectively targets tumorigenic cell as opposed to non-tumorigenic cells and is safe and tolerable in animals. Carnosol has been shown to elicit chemopreventive effects by (1) blocking the bioactivation of carcinogens, (2) enhancing antioxidant and/or detoxification enzyme activities, (3) suppressing tumor-promoting inflammation, (4) inhibiting cell proliferation and inducing apoptosis selectively in cancer cells, and (5) blocking tumor angiogenesis and invasion.

Tetrahydropalmatine is a tetrahydroprotoberberine isoquinoline alkaloid that is a primary active constituent of herbal preparations containing plant species of the genera Stephania and Corydalis. The levo isomer of THP (L-THP) appears to contribute to many of the therapeutic effects of these preparations. The pharmacological profile of L-THP, which includes antagonism of dopamine D1 and D2 receptors and actions at dopamine D3, suggests that it may have utility for treating addiction. Clinical trials where L-THP was used for the treatment of cocaine and heroin addiction have promising results. The clinical trial is planned for the treatment of schizophrenia. L-Tetrahydropalmatine is recorded in the Chinese pharmacopoeia.

Echinomycin is a cyclic peptide of the family of quinoxaline antibiotics that was originally isolated from Streptomyces echinatus. It is thought to act as a bifunctional DNA intercalator. Echinomycin has a binding site size of four base pairs. The strong binding sites for echinomycin contain the central two-base-pair sequence 5'-CG-3'. Echinomycin interferes with HIF-1 DNA binding in a sequence-specific fashion. It was brought into clinical trials by the NCI 20 years ago based on its antitumor activity. It has been extensively tested in phase I-II clinical trials. Nausea, vomiting, reversible liver enzyme abnormalities, and allergic reactions were the most common toxicities encountered. However, minimal or no antitumor activity was found in phase II clinical trials.

ICI-118551 is a selective β2 adrenergic receptor antagonist, that was originally developed for the regulation of blood pressure. ICI-118551 crosses the blood-brain barrier and it was in phase I clinical trials for the treatment of chronic anxiety. Currently, ICI-118,551 has no known therapeutic use in humans although it has been used widely in research to understand the action of the β2 adrenergic receptor, as few other specific antagonists for this receptor are known.

2-(4,6-DIMETHYLPYRIMIDIN-2-YL)-5-((2-FLUORO-6-(2H-1,2,3-TRIAZOL-2-YL)PHENYL)CARBONYL)OCTAHYDROPYRROLO(3,4-C)PYRROLE (Seltorexant, MIN 202), a small molecule, selective orexin receptor type-2 antagonist, is being developed by Minerva Neurosciences and Janssen Research & Development for the treatment of insomnia and major depressive disorder. Seltorexant has shown high in vitro affinity (affinity pKi =8.0 and 6.1 for OX2R and OX1R respectively) for the human OX2R and approximates two logs selectivity ratio versus its affinity for the OX1R. Seltorexant demonstrated a dose-dependent normalization of sleep and a trend towards improvement of subjective depressive symptoms in antidepressant-treated MDD patients with residual insomnia. Additionally, seltorexant’s favorable PK profile as a potential sedative-hypnotic drug was confirmed in a MDD population and did not demonstrate unacceptable adverse events or unwanted next-day CNS effects. Seltorexant is in phase II clinical trials for both insomnia and MDD.

SGX523 is a selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase. SGX523 was able to inhibit HGF-induced cell migration and cell scatter. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers. The clinical development of SGX523, however, was discontinued at Phase I due to renal toxicity manifested by an early rise of serum blood urea nitrogen and creatinine.

(+)-selfotel ((+)-CGS-19755) is an enantiomer of selfotel, a competitive antagonist at N-methyl-D-aspartate (NMDA)-preferring receptors. The inhibition of NMDA-evoked ACh release from rat striatal slices is stereospecific, with the (+)-enantiomer less potent than the (-)-enantiomer.

Icaritin is a monoprenylated favonol with 4′-methoxyl from Epimedium Genus. It has been documented to have osteoblastic and neuroprotective activities. It can reduce the incidence of steroid-associated oesteonecrosis in rabbit with inhibition of both intravascular thrombosis and extravascular lipid deposition for maintaining the integrity of intraosseous vasculature. Icaritin shows anti-infammatory activity and inhibitory activities against cancer cells. The phase III clinical trial is planned for the treatment of Hepatocellular carcinoma.