2 research outputs found
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