MK-2206 is an oral selective allosteric inhibitor of Akt that targets all three isoforms of human Akt (Akt-1, Akt-2 and Akt-3). In a phase I study of solid tumors, MK-2206 demonstrated evidence of target modulation and anti-proliferative activity as a single agent and in combination with other agents. Current ongoing trials of MK-2206 include monotherapy and combination therapy in breast cancer, colorectal cancer, haematological malignancies, non-small cell lung cancer and other. Detected treatment-related adverse event are: rash, fatigue, hyperglycemia.

Calcium Cation Ca-47 is a rare calcium radioactive isotope which used in orthopaedics for bone formation evaluation. Calcium-47 has a half-life of about five days, which is long enough for numerous biological investigations and short enough to ensure that the person subjected to the investigation is not under prolonged irradiation. It emits gamma rays in addition to beta rays, and since the gamma rays are capable of penetrating many centimeters of tissue, determination of calcium-47 in the body is possible by external measurements. Unfortunately, calcium-47 is difficult to produce and did not use in routine medical practice

LXR-623 is a is a highly selective and orally bioavailable synthetic agonist of Liver X receptors (LXR) alpha and beta that has shown promise in animal models of atherosclerosis. In nonhuman primates with normal lipid levels, LXR-623 significantly reduced total (50-55%) and LDL-cholesterol (LDLc) (70-77%) in a time- and dose-dependent manner and increased expression of the target genes ABCA1 and ABCG1 in peripheral blood cells of rats, mice and monkeys. LXR-623 demonstrated efficacy for reducing lesion progression in the murine LDLR(-/-) atherosclerosis model with no associated increase in hepatic lipogenesis either in this model or Syrian hamsters and displayed a unique and favorable pharmacological profile suggesting it may be suitable for evaluation in patients with atherosclerotic dyslipidemia. Results from a single ascending-dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR-623 in healthy humans confirmed the effect of LXR-623 concentration on ABCA1 and ABCG1 expression. LXR-623 was absorbed rapidly with peak concentrations (Cmax) achieved at about 2 hours and increased Cmax and area under the concentration-time curve in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. Central nervous system—related adverse events were observed at the 2 top doses tested. LXR-623 showed brain penetration and caused tumor regression in a glioblastoma (GBM) mouse model which characterize it as a potentially potent, highly-specific anti-GBM therapy.

Dibrospidium (Spyrobromin) is a dispirotripiperazine derivative and alkylating agent with potential antineoplastic and anti-inflammatory activities. The duration of DNA synthesis inhibition in tumor cells was found to correlate with spirobromine antitumor activity. Spirobromin is superior to prospidin by the power of the anti-inflammatory effect. Spyrobromin can diminish the latent period of the development of tumours in the experimental rats at intraperitoneal administration. At intragastric administration of the drug no decrease was noted in the latent period and no increase of tumours was observed in the experimental groups of the animals as compared with control. Dibrospidium has been examined for the treatment of bone cancer. The oral route of administration is the most safe with respect to the oncogenic risk. It was noted that spirobromin exerted the most pronounced toxic action on erythrocytes. Dibrospidium is used for the treatment of acute leukemias (mainly in combination therapy), malignant lymphomas, laryngeal cancer and skin reticulosis.

PF-03654764 binds with high affinity to the human H3 receptor and with lower affinity to the rat H3 receptor, in addition to having >1000-fold selectivity versus other human histamine receptor subtypes (H1, H2, and H4). PF-03654764 displayed potent antagonist properties in functional assays measuring cAMP utilizing a reporter gene assay (β-lactamase) in HEK293 cells stably expressing full length human or rat H3 receptors. In human hepatic microsomes, PF-03654764 was metabolically stable and were predicted to have low clearance. It has low potential to inhibit activities of CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4. PF-03654764 + fexofenadine failed to provide superior relief of allergic rhinitis-associated nasal symptoms upon exposure to ragweed pollen compared to fexofenadine + pseudoephedrine. Side effects in the PF-03654764-treated groups were clinically significant compared to the controls. PF-03654764 had been in phase II clinical trial for the treatment of allergic rhinitis and in phase I clinical trial for the treatment of Alzheimer's disease. However, these investigations were discontinued.

PF-232798 is a potent oral CCR5 antagonist with a primary and selectivity/safety pharmacology profile similar to maraviroc (MVC). PF-232798 shows increased binding affinity and improved oral absorption compared to maraviroc. In addition, it retains activity against a laboratory generated maraviroc-resistant HIV-1 strain, indicating an alternative drug resistance profile. PF-232798 binds to the same pocket as MVC within the transmembrane region of CCR5, but shows additional interactions at the ECL2 hinge region. PF-232798 is well tolerated in normal volunteers. PF-232798 had been in a phase-II clinical trial for the treatment of HIV infections. However, this development was discontinued.

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.