9 research outputs found
In Vitro Antiviral Activity of the Novel, Tyrosyl-Based Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor Brecanavir (GW640385) in Combination with Other Antiretrovirals and against a Panel of Protease Inhibitor-Resistant HIV▿
Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC50s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC50s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC50s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro
Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors
A series of thiazoloquin(az)olinones
were synthesized and found
to have potent inhibitory activity against CD38. Several of these
compounds were also shown to have good pharmacokinetic properties
and demonstrated the ability to elevate NAD levels in plasma, liver,
and muscle tissue. In particular, compound <b>78c</b> was given
to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold
in
liver and >1.2-fold in muscle versus control animals at a 2 h time
point. The compounds described herein possess the most potent CD38
inhibitory activity of any small molecules described in the literature
to date. The inhibitors should allow for a more detailed assessment
of how NAD elevation via CD38 inhibition affects physiology in NAD
deficient states
Development of Large-Scale Routes to Potent GPR119 Receptor Agonists
Practical and scalable syntheses
were developed that were used
to prepare multikilogram batches of GSK1292263A (<b>1</b>) and
GSK2041706A (<b>15</b>), two potent G protein-coupled receptor
119 (GPR119) agonists. Both syntheses employed relatively cheap and
readily available starting materials, and both took advantage of an
S<sub>N</sub>Ar synthetic strategy