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Supplementary Fig. S3 from Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor

Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species. [Mol Cancer Ther 2008;7(7):1880–9]

The capacity of pancreatic β cells to maintain glucose homeostasis during chronic physiologic and immunologic stress is important for cellular and metabolic homeostasis. Insulin receptor substrate 2 (IRS2) is a regulated adapter protein that links the insulin and IGF1 receptors to downstream signaling cascades. Since strategies to maintain or increase IRS2 expression can promote β cell growth, function, and survival, we conducted a screen to find small molecules that can increase IRS2 mRNA in isolated human pancreatic islets. We identified 77 compounds, including 15 that contained a tricyclic core. To establish the efficacy of our approach, one of the tricyclic compounds, trimeprazine tartrate, was investigated in isolated human islets and in mouse models. Trimeprazine is a first-generation antihistamine that acts as a partial agonist against the histamine H1 receptor (H1R) and other GPCRs, some of which are expressed on human islets. Trimeprazine promoted CREB phosphorylation and increased the concentration of IRS2 in islets. IRS2 was required for trimeprazine to increase nuclear Pdx1, islet mass, β cell replication and function, and glucose tolerance in mice. Moreover, trimeprazine synergized with anti-CD3 Abs to reduce the progression of diabetes in NOD mice. Finally, it increased the function of human islet transplants in streptozotocin-induced (STZ-induced) diabetic mice. Thus, trimeprazine, its analogs, or possibly other compounds that increase IRS2 in islets and β cells without adverse systemic effects might provide mechanism-based strategies to prevent the progression of diabetes.

A rapid and convenient palladium catalysed method for the regioselective synthesis of a range of usefully functionalised, homochiral 4-substituted 1,2-isothiazoline-3-ones is reported. The totally diastereoselective Diels-Alder reactivity of semi-cyclic sulfoxide containing dienes, 4-vinyl-1,2-isothiazoline-3-one-1-oxides is discussed.

Activated 2-(N-acylamino)-1-thia-1,3-dienes undergo efficient diastereoselective Diels-Alder cycloadditions giving access to thiopyrans of high optical purity. By variation of the position and nature of the chiral auxiliaries we have been able to induce a high degree of facial selectivity in endo selective cycloadditions and induce total facial control in exo selective cycloadditions.

4-Phenyl-2-N-(R-(−)-α-(2-naphthyl)ethylamino)-1-thia-1,3-dienes when activated by acetyl chloride, undergo extremely efficient diastereoselective exo Diels-Alder cycloadditions giving access to thiopyrans of high optical purity.

Semi cyclic sulphoxide containing dienes, 4-vinyl- 1,2-isothiazoline-3-one-1-oxides, generated in situ via Stille coupling methodology dimerise with remarkably high diastereoselectivity via an unusual exo syn transition state. X-ray analysis confirms the diastereoselectivity which was predicted by semi-empirical transition state calculations.

A rapid and convenient palladium catalysed method for the regioselective synthesis of a range of usefully functionalised, homochiral 4-substituted 1,2-isothiazoline-3-ones is reported.

4-Phenyl-2-N-(R-(−)-α-(2-naphthyl)ethylamino)-1-thia-1,3-dienes when activated by acetyl chloride, undergo extremely efficient diastereoselective exo Diels-Alder cycloadditions giving access to thiopyrans of high optical purity.

A novel Pd(0)-catalyzed carbonylation of both isolable 1,2-diaza-1,3-butadienes and those generated in situ by extrusion of SO2 and CO2 from heterocyclic precursors is described. The reaction proceeds at room temperature to 110 °C under 1−2 atm of CO to afford 2,3-pyrazol-1(5H)-ones in good to excellent yields. The effect of catalyst structure and stability on the carbonylation reaction is evaluated.

[reaction--see text] [corrected] The preparation and thermolysis of new stable heterocyclic precursors of 1,2-diaza-1,3-butadienes is described. The resulting reactive diazadienes are trapped in situ with N-phenylmaleimide [corrected]. The effect of precursor structure on the temperature at which the diazadienes are generated is discussed.

Publisher Summary Melatonin is widely used as an over-the-counter therapy for the treatment of sleep disorders. This chapter discusses the use of melatonin and synthetic melatonin agonists for the treatment of sleep, major depression and anxiety. The hormone melatonin 1 (N-acetyl-5-methoxytryptamine) is produced and secreted from the pinealocytes of the pineal gland. Melatonin is synthesized in a circadian mode as it is produced at high levels at night and low levels during the day. Melatonin has high affinity for two G-protein coupled receptors (GPCRs), designated MT1 and MT2, and activates the inhibition of adenylyl cyclase via these receptors. Melatonin receptors MT1 and MT2 have amino acid sequences which are 60% identical. In situ analysis has revealed that MT1 mRNA is present in human suprachiasmatic nucleus (SCN). The distinct function of MT1 and MT2 has yet to be clearly defined; however, their role in the regulation of sleep and in circadian rhythm is well established. Melatonin has been studied extensively as close indole containing analogs have also been reported in the literature. The melatonin agonist LY-156735, 2 was recently reported to alleviate the symptoms of shift lag and to help resynchronize circadian rhythms at a dose of 5 mg/day in human clinical trials.

[reaction--see text] [corrected] The preparation and thermolysis of new stable heterocyclic precursors of 1,2-diaza-1,3-butadienes is described. The resulting reactive diazadienes are trapped in situ with N-phenylmaleimide [corrected]. The effect of precursor structure on the temperature at which the diazadienes are generated is discussed.

[reaction--see text] A novel Pd(0)-catalyzed carbonylation of both isolable 1,2-diaza-1,3-butadienes and those generated in situ by extrusion of SO(2) and CO(2) from heterocyclic precursors is described. The reaction proceeds at room temperature to 110 degrees C under 1-2 atm of CO to afford 2,3-pyrazol-1(5H)-ones in good to excellent yields. The effect of catalyst structure and stability on the carbonylation reaction is evaluated.