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.

MK-8325 is tricyclic silyl compound patented by Schering Corporation as an antiviral agent for treating hepatitis C virus infection. MK-8325 acts as a potent hepatitis C virus nonstructural protein 5A (NS5A) inhibitor with excellent replicon activity across multiple genotypes. The compound is orally absorbed from the GI tracts of rats, dogs, and cynomolgus monkeys with low to moderate bioavailability. MK-8325 showed high protein binding in all species and is highly distributed to the target organ with minimal or no brain distribution In vitro and in vivo assays showed MK-8325 to be orally bioavailable with pharmacokinetics suitable for once-daily dosing in patients and good overall ADME profiles.

PM-00104 (Zalypsis®) is a synthethic tetrahydroisoquinolone alkaloid, which is structurally similar to many marine organisms. PM-00104 is a DNA binding agent, causing inhibition of the cell cycle and transcription, which can lead to double stranded DNA breaks. Immunohistochemical studies in tumors also demonstrated histone-H2AX phosphorylation and p53 overexpression. PM-00104 has progressed into phase II clinical trials to treat Ewing sarcoma, urothelial carcinoma, multiple myeloma, endometrial and cervical cancer. The phase II study concluded that there were no objective responses in the cohort of 16 evaluable patients with Ewing sarcoma. The study of Urothelial carcinoma treatment was terminated early because there seemed to be no benefit from the current therapy. Moreover, PM-00104 as a single-agent did not prove to be an effective therapy for patients with advanced/metastatic endometrial or cervical cancer. None achieved objective tumor response was in phase II study for the treatment of advanced/metastatic endometrial or cervical cancer. Preliminary data showed PM-00104 to be safe to use in the treatment of multiple myeloma but the complete results from this trial have not been published.

Centanafadine is an oral triple reuptake inhibitor that has been developed by DOV Pharmaceutical as a treatment for attention-deficit hyperactivity disorder (ADHD). Centanafadine works by modulating the activity of norepinephrine, dopamine, and serotonin, three neurotransmitters known to be relevant in patients with ADHD. In the human abuse liability study, immediate-release centanafadine demonstrated a reduced abuse potential compared with the schedule II stimulants d-amphetamine and lisdexamfetamine. Treatment with high doses of immediate-release centanafadine resulted in a markedly different profile than that of the comparators, with most subjects experiencing the acute onset of adverse effects, including nausea, vomiting, and dysphoria. Almost 2 hours after the administration of centanafadine, the test subjects reported “liking” at about two-thirds of the magnitude of amphetamines, a finding that may have indicated dopamine activity. However, unlike amphetamines, which provided an immediate positive experience, the subjects receiving centanafadine experienced negative effects before reaching that point.

CC-115 is a recently identified inhibitor of the mammalian Target of Rapamycin Kinase (TORK) and DNA-Dependent Protein Kinase (DNA-PK). It is under investigation in phase II clinical trials for the treatment for Glioblastoma and in phase I trials for the treatment of prostate cancer, Ewing's, Osteosarcoma, Chronic Lymphocytic Leukemia and Squamous Cell Carcinoma of the Head and Neck.

G-0853 (also GDC-0853, or Fenebrutinib) is a potent, selective, orally administered, and noncovalent Bruton's tyrosine kinase (Btk) inhibitor currently in clinical development. Upon administration, G-0853 inhibits the activity of Btk and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and Btk-mediated activation of downstream survival pathways, which leads to the inhibition of the growth of malignant B-cells that overexpress BTK. BTK is overexpressed in B-cell malignancies, and plays an important role in B-lymphocyte development, activation, signaling, proliferation and survival. G-0853 suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. G-0853 demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria.