AVN-944 is an IMPDH (inosine 5-monophosphate dehydrogenase) inhibitor which is now being tested in phase I of clinical trials for the treatment of hematologic malignancies and solid tumors and in phase II for pancreatic cancer (in combination with gemcitabine). The drug showed good inhibition of IMPDH isoforms I and II with Ki=6-10 nM.

Medorinone is an inhibitor of cAMP phosphodiesterase activity. Inhibition of cAMP phosphodiesterase by medorinone in cardiac and vascular smooth muscle is a mechanism by which this agent produces both positive cardiac inotropy and vascular smooth muscle relaxation. It inhibits platelet aggregation.

ISBOGREL is a specific thromboxane A2 synthetase inhibitor. Its clinical development was discontinued, although it was a suitable candidate for clinical trials in cardiovascular diseases in which imbalance between thromboxane and prostacyclin may be involved in the pathogenesis.

Tolfamide is a benzamide and urease enzyme inhibitor.

Pyroxamide is a potent histone deacetylase (HDAC) inhibitor. Pyroxamide induced terminal differentiation in murine erythroleukemia (MEL) cells and inhibited the growth by cell cycle arrest or apoptosis in a variety of tumor cells. An accumulation of acetylated histones and increased levels of p21/WAF1 expression were detected in cancer cells and in prostate xenografts treated with Pyroxamide.

Cipamfylline is a xanthine, a theophylline analogue, and is a potent and selective inhibitor of phosphodiesterase type 4 (PDE-4). Cipamfylline was tested in patients with a diagnosis of atopic dermatitis and in two human models of acute and chronic irritant contact dermatitis. The outcome of the study revealed that cipamfylline was more effective than vehicle in treating atopic dermatitis, but less effective than a group II steroid, hydrocortisone-17-butyrate both in the treatment of atopic dermatitis and irritant contact dermatitis. The absorption of cipamfylline and the subsequent systemic exposure might be the reason why further clinical studies with higher doses of cipamfylline have not been published.

6-O-BENZYLGUANINE is a guanine analogue with antineoplastic activity. O(6)-benzylguanine binds the DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT), transferring the benzyl moiety to the active-site cysteine and resulting in inhibition of AGT-mediated DNA repair. Co-administration of this agent potentiates the effects of other chemotherapeutic agents that damage DNA. 6-O-benzylguanine has been used in trials studying the treatment of HIV Infection, Adult Gliosarcoma, Adult Glioblastoma, Stage I Adult Hodgkin Lymphoma, and Stage II Adult Hodgkin Lymphoma, among others.

Plevitrexed is a rationally designed, orally bioavailable, nonpolyglutamatable quinazoline antifolate that is a selective inhibitor of thymidylate synthase with potent antineoplastic activity and the ability to overcome antifolate resistance due to decreased folylpolyglutamate synthetase activity. It also features a lower toxicity than polyglutamatable thymidylate synthase inhibitors, presumably due to a lesser cellular retention. Plevitrexed is primarily transported into the cells via reduced folate carrier and selectively binds to the folate-binding site of thymidylate synthase with high affinity. Plevitrexed was assessed and in preclinical studies against a panel of human ovarian cancer cell lines and in several phase II clinical studies for the treatment of various solid cancers including colorectal, gastric, pancreatic and ovarian cancer. The combination of plevitrexed and carboplatin is well tolerated with no significant pharmacokinetic interaction between the two drugs - antitumor activity in platinum-pretreated gynecological malignancy was demonstrated.

Daporinad is an inhibitor of nicotinamide phosphoribosyltransferase (NMPRTase), an enzyme that participates in the biosynthesis of nicotinamide adenine dinucleotide (NAD+) from niacinamide (vitamin B3). Inhibition of NMPRTase may deplete energy reserves in metabolically active tumor cells and induce tumor cell apoptosis. In addition, this agent may inhibit tumor cell production of vascular endothelial growth factor (VEGF), resulting in the inhibition of tumor angiogenesis. Daporinad was investigated as a treatment of B-cell chronic lymphocytic leukemia, melanoma, and cutaneous T-cell lymphoma. Clinical trials have shown that drug has low efficacy when used alone.

Galunisertib is a potent inhibitor of TGF beta type 1 receptor. The drug is under clinical development for the treatment of different cancers: pancreatic, hepatocellular, breast, rectal, prostate etc. and reached phase 2/3 in patients with myelodysplastic syndromes.