Scott H. Allen

The use of oxadiazole and triazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 1: Establishing the pharmacophore.

A series of HIV-1 integrase inhibitors containing a novel metal binding motif consisting of the 8-hydroxy-1,6-naphthyridine core and either an oxadiazole or triazole has been identified. The design of the key structural components was based on a two-metal coordination pharmacophore. This report presents initial structure-activity data that shows the new chelation architecture delivers potent inhibition in both enzymatic and antiviral assays.

The Naphthyridinone GSK364735 Is a Novel, Potent Human Immunodeficiency Virus Type 1 Integrase Inhibitor and Antiretroviral

ABSTRACT The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration ± standard deviation, 8 ± 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd [binding constant], 6 ± 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 ± 0.4 and 5 ± 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.

1,3,4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position

The use of a 1,3,4-oxadiazole in combination with an 8-hydroxy-1,6-naphthyridine ring system has been shown to deliver potent enzyme and antiviral activity through inhibition of viral DNA integration. This report presents a detailed structure-activity investigation of the C5 position resulting in low nM potency for several analogs with an excellent therapeutic index.

Synthesis and evaluation of 7-substituted-3-cyclobutylamino-4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives as KATP channel agonists

A series of 7-substituted-3-cyclobutylamino-4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives has been synthesized and evaluated as K(ATP) channel agonists using the inside-out excised patch clamp technique. The most active compounds were approximately 20-fold more potent than diazoxide in opening K(ATP) channels. A linear relationship exists between the potency of the compound and the sigma value of the 7-substituent with electron-withdrawing groups exhibiting higher activity. These compounds may be useful in modulating insulin release from pancreatic beta-cells and in diseases associated with hyperinsulinemia.

Physics of bipolar, unipolar and intermediate conduction modes in Silicon Carbide MOSFET body diodes

This paper details the device physics of Silicon Carbide MOSFETs in third quadrant operation. It is observed that the gate bias has a large effect on controlling the injection efficiency at the anode of the body diode. The change in threshold voltage due to body-effect and the voltage drop across the anode junction play a key role in controlling the balance between electron and hole currents at the anode end, which gives the device the capability to operate in unipolar, bipolar or intermediate conduction modes depending on current density and operating temperature.

Impact of carrier lifetime enhancement using high temperature oxidation on 15 kV 4H-SiC P-GTO thyristor

The impact of the lifetime enhancement process using high temperature thermal oxidation method on 4H-SiC P-GTOs was investigated. 15 kV 4H-SiC P-GTOs with 140 μm thick drift layers, with and without 1450°C lifetime enhancement oxidation (LEO) process, were compared. The LEO process increased the average carrier lifetime in p-type epi layer from 0.9 μs to 6.25 μs, and it was observed that the effectiveness of the lifetime enhancement process was very sensitive to the doping concentration. The device with the LEO process showed a significant reduction in forward voltage drop and a substantially lower holding current, as expected from the carrier lifetime measurements. However, a slight reduction in blocking capability was also observed from the devices treated with LEO process. The common emitter current gain (β) of the wide base test NPN BJT was approximately 10X higher for the wafer with LEO process.

Reliability assessment of a large population of 3.3 kV, 45 A 4H-SIC MOSFETs

In this work, we report results for the 3 lot, 77 device-per-lot high temperature-reverse bias (HTRB) test, as well as work on gate oxide reliability for 3.3 kV devices in relation to the presence of material defects. The work indicates that large scale reliable operation of 3.3 kV 4H-SIC MOSFETs is achievable using conventional 4H-SiC device processing techniques and DMOS device structures, despite the prevalence of measurable surface morphology on 3.3 kV SiC epilayers. No correlation was found between dislocation content and MOS capacitor breakdown field, measured on over 14 cm2 of combined tested 4H-SIC MOS gate area.

Record-low 10mΩ SiC MOSFETs in TO-247, rated at 900V

We demonstrate a 900V SiC MOSFET with a record-low ON resistance of 10 mΩ in a TO-247 package. Due to their record low specific ON resistance, and a low Rds,On temperature coefficient, 900V SiC MOSFETs can far exceed the current densities of IGBTs in discrete packages. SiC MOSFETs also have a robust, low reverse recovery body diode which makes them suited to hard-switched and soft-switched topologies with bi-directional conduction. They can also achieve superior light load efficiencies due to knee-less conduction in both 1st and 3rd quadrant, low switching losses and low body diode reverse recovery losses.

Electrical properties and interface structure of SiC MOSFETs with barium interface passivation

A Barium-rich interface process provides SiO2/SiC interface conditions suitable for obtaining SiC field-effect (FE) channel mobility twice that of a nitric oxide (NO) passivation anneal. The temperature dependence of the field-effect mobility indicates clear differences in their interface properties. Secondary-ion mass spectrometry (SIMS) indicates that Ba remains predominantly at the SiO2/SiC interface, with only ~1×1017 cm-3 Ba in the oxide.The interface structure and chemistry of the Ba-modified MOS devices was investigated using scanning transmission electron microscopy (STEM) and energy-dispersive X-ray spectroscopy (EDS). High-angle annular dark-field (HAADF) imaging reveals that the Ba interface layer results in an oxide-interface region not present in the NO annealed control sample. EDS mapping shows that this is a Ba-rich oxide interface layer. Using a new technique “revolving STEM” (RevSTEM) to correct drift and image distortion, SiC strain maps were generated. With an NO anneal there is tensile strain within SiC at the SiO2/SiC interface, along the C-axis direction. With the Ba interlayer, however, there is no observable strain relative to the bulk SiC. This interface strain may correlate with the inversion layer mobility, with an unstrained interface preferred.

Impact of next-generation 1700V SiC MOSFETs in a 125kW PV converter

1700V SiC modules were built with next-generation SiC MOSFETs, with 25°C RDSON per MOSFET cut approximately 50% from existing commercial SiC MOSFETs. Additionally, the external SiC anti-parallel diode was eliminated in favor of using the SiC MOSFET body diode during the dead time. The resulting 1700V SiC module used only 32% of the SiC chip area, yet reduced the 25°C module RDSON from 8mΩ to 5mΩ, and increased the current rating at operating temperature from 225A to 300A, compared to the previous generation module. Additionally, using a 125kW PV converter switching at 30kHz to benchmark the technologies, both generations of 1700V SiC modules were found to be approximately equal in system efficiency at 99%, +/− 0.1%.