Stimulation-produced analgesia from sites in the ventrolateral pons of the rat brain.

Stimulation-produced analgesia from sites in the ventrolateral pons of the rat brain

Low-Viscosity Route to High-Molecular-Weight Water-Soluble Polymers: Exploiting the Salt Sensitivity of Poly(<i>N</i>‑acryloylmorpholine)

We report a new one-pot low-viscosity synthetic route to high molecular weight non-ionic water-soluble polymers based on polymerization-induced self-assembly (PISA). The RAFT aqueous dispersion polymerization of N-acryloylmorpholine (NAM) is conducted at 30 °C using a suitable redox initiator and a poly­(2-hydroxyethyl acrylamide) (PHEAC) precursor in the presence of 0.60 M ammonium sulfate. This relatively low level of added electrolyte is sufficient to salt out the PNAM block, while steric stabilization is conferred by the relatively short salt-tolerant PHEAC block. A mean degree of polymerization (DP) of up to 6000 was targeted for the PNAM block, and high NAM conversions (>96%) were obtained in all cases. On dilution with deionized water, the as-synthesized sterically stabilized particles undergo dissociation to afford molecularly dissolved chains, as judged by dynamic light scattering and 1H NMR spectroscopy studies. DMF GPC analysis confirmed a high chain extension efficiency for the PHEAC precursor, but relatively broad molecular weight distributions were observed for the PHEAC–PNAM diblock copolymer chains (Mw/Mn > 1.9). This has been observed for many other PISA formulations when targeting high core-forming block DPs and is tentatively attributed to chain transfer to polymer, which is well known for polyacrylamide-based polymers. In fact, relatively high dispersities are actually desirable if such copolymers are to be used as viscosity modifiers because solution viscosity correlates closely with Mw. Static light scattering studies were also conducted, with a Zimm plot indicating an absolute Mw of approximately 2.5 × 106 g mol–1 when targeting a PNAM DP of 6000. Finally, it is emphasized that targeting such high DPs leads to a sulfur content for this latter formulation of just 23 ppm, which minimizes the cost, color, and malodor associated with the organosulfur RAFT agent

Synthesis of HCV Replicase Inhibitors: Base-Catalyzed Synthesis of Protected α‑Hydrazino Esters and Selective Aerobic Oxidation with Catalytic Pt/Bi/C for Synthesis of Imidazole-4,5-dicarbaldehyde

A robust convergent synthesis of the prodrugs of HCV replicase inhibitors <b>1</b>–<b>5</b> is described. The central 5<i>H</i>-imidazo­[4,5-<i>d</i>]­pyridazine core was formed from acid-catalyzed cyclocondensation of an imidazole-4,5-dicarbaldehyde (<b>20</b>) and a α-hydrazino ester, generated in situ from the bis-BOC-protected precursors <b>25</b> and <b>33</b>. The acidic conditions not only released the otherwise unstable α-hydrazino esters but also were the key to avoid facile decarboxylation to the parent drugs from the carboxylic ester prodrugs <b>1</b>–<b>5</b>. The bis-BOC α-hydrazino esters <b>25</b> and <b>33</b> were prepared by addition of ester enolates (from <b>23</b> and <b>32</b>) to di-<i>tert</i>-butyl azodicarboxylate via catalysis with mild inorganic bases, such as Li₂CO₃. A selective aerobic oxidation with catalytic 5% Pt–Bi/C in aqueous KOH was developed to provide the dicarbaldehyde <b>20</b> from the diol <b>27</b>

Imidazopyridazine Hepatitis C Virus Polymerase Inhibitors. Structure–Activity Relationship Studies and the Discovery of a Novel, Traceless Prodrug Mechanism

By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented

Hepatitis C Replication Inhibitors That Target the Viral NS4B Protein

We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead <b>1a</b>. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound <b>1a</b> was transformed into (+)-<b>28a</b> which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric “humanized” mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection