Diazepam (Valium) is among the most successful drugs from the onset of the psychopharmacological revolution that began during the 1950s. Efficacious in treating a wide-spectrum of CNS disorders, including anxiety and epilepsy, it set the standard for pharmacotherapy in terms of potency, onset of action, and safety. In this Review, the legacy of diazepam to chemical neuroscience will be considered along with its synthesis, pharmacology, drug metabolism, adverse events and dependence, clinical use, and regulatory issues.

Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.

The novel T-type antagonist ( S)- 5 has been prepared and evaluated in in vitro and in vivo assays for T-type calcium ion channel activity. Structural modification of the piperidine leads 1 and 2 afforded the fluorinated piperidine ( S)- 5, a potent and selective antagonist that displayed in vivo CNS efficacy without adverse cardiovascular effects.

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The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and decreasing cell-cell adhesion. This action is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor liver kinase B1 (LKB1). Accordingly, inhibitors of IP6K2 offer promise in cancer therapy.I nositol pyrophosphates, conserved eukaryotic messenger molecules with a pyrophosphate bond, mediate numerous physiologic processes including regulation of Akt (1), insulin secretion (2), ATP production (3), DNA repair (4), and damage response (5). Exemplified by diphosphoinositol pentakisphosphate (PPIP5, IP7), inositol pyrophosphates are primarily generated by a family of three inositol hexakisphosphate (IP6) kinases (IP6K) (6, 7) and also may be formed by a more recently described group of IP6/7 kinases (8). IP6K1 and IP6K2 are widely distributed, whereas IP6K3 is expressed primarily in the brain (9). A related enzyme, inositol polyphosphate multikinase (IPMK), converts IP3 to IP4 and IP5, displays physiologic PI3 kinase activity (10), and noncatalytically acts as a transcriptional coactivator (11) and stabilizer of the mTOR complex-1 (12). Whether IP6Ks and IPMK play direct roles in tumor progression remains unexplored.Tumor cell metastasis requires loss of cell-cell adhesion and gain of migratory and invasive properties, a collective program known as epithelial-mesenchymal transition (EMT), which is also critical for embryonic development (13). Cell-cell adhesion and cell migration/invasion are primarily driven by E-cadherinmediated cell clustering (14) and focal-adhesion-based cellmatrix interactions (15), respectively. Whether these two distinct adhesion processes are concurrently or independently regulated remains poorly understood.The tumor suppressor LKB1 has been separately reported to inhibit FAK activation (16) and to enhance E-cadherin expression (17)(18)(19). LKB1 is mutated in Peutz-Jeghers syndrome patients who tend to develop cancer at multiple sites (20). As a master kinase controlling the activity of AMPK and 13 other AMPK-like kinases (21), LKB1 mediates diverse cellular processes such as polarity, adhesion, metabolism, tumor growth/metastasis, and neuronal axon initiation/branching (22). Unlike conventional protein kinases, LKB1 is not activated by activation loop phosphorylation but by protein-protein interaction with two other subunits of the heterotrimeric holoenzyme: STRAD and Mo25. LKB1 can also exist as an inactive nuclear monomer. STRAD binds and stabilizes LKB1 (23) in the cytosol, where it is phosphorylated at serine 428 by PKCζ (24). Whether cytosolic localization enhance...