3 research outputs found
Identification of Inhibitors of NOD1-Induced Nuclear Factor-κB Activation
NOD1 (nucleotide-binding oligomerization domain 1) protein is a member of the NLR (NACHT and leucine rich repeat domain containing proteins) protein family, which plays a key role in innate immunity as a sensor of specific microbial components derived from bacterial peptidoglycans and induction of inflammatory responses. Mutations in NOD proteins have been associated with various inflammatory diseases that affect NF-κB (nuclear factor κB) activity, a major signaling pathway involved in apoptosis, inflammation, and immune response. A luciferase-based reporter gene assay was utilized in a high-throughput screening program conducted under the NIH-sponsored Molecular Libraries Probe Production Center Network program to identify the active scaffolds. Herein, we report the chemical synthesis, structure–activity relationship studies, downstream counterscreens, secondary assay data, and pharmacological profiling of the 2-aminobenzimidazole lead (compound <b>1c</b>, ML130) as a potent and selective inhibitor of NOD1-induced NF-κB activation
Discovery of a Plasmodium falciparum Glucose-6-phosphate Dehydrogenase 6‑phosphogluconolactonase Inhibitor (<i>R</i>,<i>Z</i>)‑<i>N</i>‑((1-Ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro‑2<i>H</i>‑benzo[<i>b</i>][1,4]thiazine-6-carboxamide (ML276) That Reduces Parasite Growth in Vitro
A high-throughput screen of the NIH’s MLSMR collection
of
∼340000 compounds was undertaken to identify compounds that
inhibit Plasmodium falciparum glucose-6-phosphate
dehydrogenase (<i>Pf</i>G6PD). <i>Pf</i>G6PD is
important for proliferating and propagating P. falciparum and differs structurally and mechanistically from the human orthologue.
The reaction catalyzed by glucose-6-phosphate dehydrogenase (G6PD)
is the first, rate-limiting step in the pentose phosphate pathway
(PPP), a key metabolic pathway sustaining anabolic needs in reductive
equivalents and synthetic materials in fast-growing cells. In P. falciparum, the bifunctional enzyme glucose-6-phosphate
dehydrogenase-6-phosphogluconolactonase (<i>Pf</i>GluPho)
catalyzes the first two steps of the PPP. Because P.
falciparum and infected host red blood cells rely
on accelerated glucose flux, they depend on the G6PD activity of <i>Pf</i>GluPho. The lead compound identified from this effort,
(<i>R</i>,<i>Z</i>)-<i>N</i>-((1-ethylpyrrolidin-2-yl)Âmethyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2<i>H</i>-benzoÂ[<i>b</i>]Â[1,4]Âthiazine-6-carboxamide, <b>11</b> (ML276), is a submicromolar inhibitor of <i>Pf</i>G6PD (IC<sub>50</sub> = 889 nM). It is completely selective for the
enzyme’s human isoform, displays micromolar potency (IC<sub>50</sub> = 2.6 μM) against P. falciparum in culture, and has good drug-like properties, including high solubility
and moderate microsomal stability. Studies testing the potential advantage
of inhibiting <i>Pf</i>G6PD in vivo are in progress
Discovery of ML314, a Brain Penetrant Nonpeptidic β‑Arrestin Biased Agonist of the Neurotensin NTR1 Receptor
The neurotensin 1 receptor (NTR1) is an important therapeutic target
for a range of disease states including addiction. A high-throughput
screening campaign, followed by medicinal chemistry optimization,
led to the discovery of a nonpeptidic β-arrestin biased agonist
for NTR1. The lead compound, 2-cyclopropyl-6,7-dimethoxy-4-(4-(2-methoxyphenyl)-piperazin-1-yl)Âquinazoline, <b>32</b> (ML314), exhibits full agonist behavior against NTR1 (EC<sub>50</sub> = 2.0 μM) in the primary assay and selectivity against
NTR2. The effect of <b>32</b> is blocked by the NTR1 antagonist
SR142948A in a dose-dependent manner. Unlike peptide-based NTR1 agonists,
compound <b>32</b> has no significant response in a Ca<sup>2+</sup> mobilization assay and is thus a biased agonist that activates the
β-arrestin pathway rather than the traditional G<sub><i>q</i></sub> coupled pathway. This bias has distinct biochemical
and functional consequences that may lead to physiological advantages.
Compound <b>32</b> displays good brain penetration in rodents,
and studies examining its in vivo properties are underway