133550-40-0Relevant articles and documents
Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties
Eleftheriadis, Nikolaos,Poelman, Hessel,Leus, Niek G.J.,Honrath, Birgit,Neochoritis, Constantinos G.,Dolga, Amalia,D?mling, Alexander,Dekker, Frank J.
, p. 786 - 801 (2016/08/30)
The enzyme 15-lipoxygenase-1 (15-LOX-1) plays a dual role in diseases with an inflammatory component. On one hand 15-LOX-1 plays a role in pro-inflammatory gene expression and on the other hand it has been shown to be involved in central nervous system (CNS) disorders by its ability to mediate oxidative stress and damage of mitochondrial membranes under hypoxic conditions. In order to further explore applications in the CNS, novel 15-LOX-1 inhibitors with favorable physicochemical properties need to be developed. Here, we present Substitution Oriented Screening (SOS) in combination with Multi Component Chemistry (MCR) as an effective strategy to identify a diversely substituted small heterocyclic inhibitors for 15-LOX-1, denoted ThioLox, with physicochemical properties superior to previously identified inhibitors. Ex?vivo biological evaluation in precision-cut lung slices (PCLS) showed inhibition of pro-inflammatory gene expression and in?vitro studies on neuronal HT-22?cells showed a strong protection against glutamate toxicity for this 15-LOX-1 inhibitor. This provides a novel approach to identify novel small with favorable physicochemical properties for exploring 15-LOX-1 as a drug target in inflammatory diseases and neurodegeneration.
Structure-activity relationship of N-(phenylalkyl)cinnamides as novel NR2B subtype-selective NMDA receptor antagonists
Tamiz, Amir P.,Cai, Sui Xiong,Zhou, Zhang-Lin,Yuen, Po-Wai,Schelkun, Robert M.,Whittemore, Edward R.,Weber, Eckard,Woodward, Richard M.,Keana, John F. W.
, p. 3412 - 3420 (2007/10/03)
A novel series of N-(phenylalkyl)cinnamides related to N-(4- phenylbutyl)-3,4-dihydroxy-β-cyanocinnamide (6, an EGFR-K inhibitor with high antiproliferative activity) was synthesized and tested for antagonism at N-methyl-D-aspartate (NMDA) receptor subtypes. Potency and subunit selectivity were assayed by electrical recordings in Xenopus oocytes expressing three binary combinations of cloned rat NMDA receptor subunits: NR1A expressed in combination with either NR2A, NR2B, or NR2C. The N- (phenylalkyl)cinnamides are selective antagonists of NR1(A)/2B receptors. Assayed under steady-state conditions, N-(4-phenylbutyl)-4-hydroxycinnamide (16) has an IC50 value of 77 nM and > 1000-fold selectivity with respect to NR1(A)/2A and NR1(A)/2C receptors. Potency at α1 adrenergic receptors is low for the four cinnamides tested. Inhibition of NR1(A)/2B receptors does not correlate with EGFR and ErbB2/neu tyrosine kinase inhibitor activity. The N-(phenylalkyl)cinnamide series we describe provides a novel and structurally diverse framework for designing new NR2B-selective NMDA antagonists as potential CNS therapeutics.
