10 research outputs found
Second Generation Tetrahydroquinoline-Based Protein Farnesyltransferase Inhibitors As Antimalarials
Substituted tetrahydroquinolines (THQs) have been previously identified as inhibitors of mammalian protein farnesyltransferase (PFT). Previously we showed that blocking PFT in the malaria parasite led to cell death and that THQ-based inhibitors are the most potent among several structural classes of PFT inhibitors (PFTIs). We have prepared 266 THQ-based PFTIs and discovered several compounds that inhibit the malarial enzyme in the sub- to low-nanomolar range and that block the growth of the parasite (P. falciparum) in the low-nanomolar range. This body of structure-activity data can be rationalized in most cases by consideration of the X-ray structure of one of the THQs bound to mammalian PFT together with a homology structural model of the malarial enzyme. The results of this study provide the basis for selection of antimalarial PFTIs for further evaluation in preclinical drug discovery assays. © 2007 American Chemical Society
2-Oxo-Tetrahydro-1,8-Naphthyridines As Selective Inhibitors Of Malarial Protein Farnesyltransferase And As Anti-Malarials
A new class of 2-oxo-tetrahydro-1,8-naphthyridine-based protein farnesyltransferase inhibitors were synthesized and found to inhibit protein farnesyltransferase from the malaria parasite with potencies in the low nanomolar range. The compounds were much less potent on mammalian protein prenyltransferases. Two of the compounds block the growth of malaria in culture with potencies in the sub-micromolar range. Some of the compounds were found to be much more metabolically stable than previously described tetrahydroquinoline-based protein farnesyltransferase inhibitors. © 2007 Elsevier Ltd. All rights reserved
5-Fluoro-2-indolyl des-chlorohalopemide (FIPI), a Phospholipase D Pharmacological Inhibitor That Alters Cell Spreading and Inhibits Chemotaxis
The signaling enzyme phospholipase D (PLD) and the lipid second messenger
it generates, phosphatidic acid (PA), are implicated in many cell biological
processes, including Ras activation, cell spreading, stress fiber formation,
chemotaxis, and membrane vesicle trafficking. PLD production of PA is
inhibited by the primary alcohol 1-butanol, which has thus been widely
employed to identify PLD/PA-driven processes. However, 1-butanol does not
always effectively reduce PA accumulation, and its use may result in
PLD-independent deleterious effects. Consequently, identification of potent
specific small-molecule PLD inhibitors would be an important advance for the
field. We examine one such here, 5-fluoro-2-indolyl des-chlorohalopemide
(FIPI), which was identified recently in an in vitro chemical screen for PLD2
inhibitors, and show that it rapidly blocks in vivo PA production with
subnanomolar potency. We were surprised to find that several biological
processes blocked by 1-butanol are not affected by FIPI, suggesting the need
for re-evaluation of proposed roles for PLD. However, FIPI does inhibit PLD
regulation of F-actin cytoskeleton reorganization, cell spreading, and
chemotaxis, indicating potential utility for it as a therapeutic for
autoimmunity and cancer metastasis
2-Oxo-tetrahydro-1,8-naphthyridines as selective inhibitors of malarial protein farnesyltransferase and as anti-malarials
Identification of 1‑({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)‑1<i>H</i>‑pyrazol-3-yl]carbonyl}amino)cyclohexane Carboxylic Acid as a Selective Nonpeptide Neurotensin Receptor Type 2 Compound
Compounds
active at neurotensin receptors (NTS1 and NTS2) exert analgesic effects
on different types of nociceptive modalities, including thermal, mechanical,
and chemical stimuli. The NTS2 preferring peptide JMV-431 (<b>2</b>) and the NTS2 selective nonpeptide compound levocabastine (<b>6</b>) have been shown to be effective in relieving the pain associated
with peripheral neuropathies. With the aim of identifying novel nonpeptide
compounds selective for NTS2, we examined analogues of SR48692 (<b>5a</b>) using a FLIPR calcium assay in CHO cells stably expressing
rat NTS2. This led to the discovery of the NTS2 selective nonpeptide
compound 1-({[1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1<i>H</i>-pyrazol-3-yl]Âcarbonyl}Âamino)Âcyclohexane carboxylic acid (NTRC-739, <b>7b</b>) starting from the nonselective compound <b>5a</b>