Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity

Hieke, Martina; Neß, Julia; Steri, Ramona; Dittrich, Michaela; Werz, Oliver; Baumann, Karlheinz; Schubert‐Zsilavecz, Manfred; Weggen, Sascha; Zettl, Heiko

doi:10.1021/jm1003073

Cited by 38 publications

(42 citation statements)

References 48 publications

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“…The p-trifluoromethyl-phenyl derivative (112) showed inhibitory activity against A 1-42 formation (IC 50 = 6 μM), activation of PPAR (EC 50 = 11μM) and weaker COX1 inhibitory activity (IC 50 = 16.9 μM). The cyclohexyl derivative (113) was the most active in this group, with A 1-42 IC 50 of 5.1 μM and PPAR EC 50 of 6.6μM, but also had higher affinity for COX1 and COX2 (IC 50 COX1 = 13,4 μM, IC 50 COX2 = 10,9 μM) [144]. However, it was also shown that these two active compounds (112,113) do not affect Notch processing or signaling in nontoxic concentrations.…”

Section: Dual Acting Hybrids --Secretase Modulators With Ppar Activitymentioning

confidence: 86%

“…A novel class of dual modulators of -secretase and peroxisome proliferator-activated receptor (PPAR ) were presented by Hieke et al [144]. One of the main objectives of this study was to develop a potent dual modulator with weaker cyclooxygenase (COX) inhibitory activity compared to non-steroidal anti-inflammatory drug (NSAIDs)-type -secretase modulators (GSM).…”

Section: Dual Acting Hybrids --Secretase Modulators With Ppar Activitymentioning

confidence: 99%

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Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

Bajda

Guzior²,

Ignasik³

et al. 2011

CMC

220

131

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Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid β peptide (Aβ) and the hyperphosphorylated tau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aβ plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H(3) receptor antagonism, cannabinoid CB(1) receptor antagonism and β-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.

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Section: Dual Acting Hybrids --Secretase Modulators With Ppar Activitymentioning

confidence: 86%

Section: Dual Acting Hybrids --Secretase Modulators With Ppar Activitymentioning

confidence: 99%

Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

Bajda

Guzior²,

Ignasik³

et al. 2011

CMC

220

131

View full text Add to dashboard Cite

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“…Monoclonal antibody IC16 raised against residues 1–15 of the human Aβ sequence, HRP-coupled carboxyl terminus-specific Aβ antibodies BAP24, BAP15 and BAP29 specific for Aβ40, Aβ42, and Aβ38, and polyclonal antibody CT15 against the last 15 C-terminal amino acids of human APP have been described previously [22], [40]. Monoclonal antibody PSN2 against a synthetic peptide corresponding to amino acids 31–56 of human PSEN1 was kindly provided by Dr. Hiroshi Mori [41].…”

Section: Methodsmentioning

confidence: 99%

Presenilin Is the Molecular Target of Acidic γ-Secretase Modulators in Living Cells

et al. 2012

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The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic Aβ42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the γ-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers Aβ42 generation with an IC50 of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the γ-secretase complex, in living cells. Labeling was not observed for APP or any of the other γ-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the γ-secretase complex.

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“…The investigated pirinixic acid derivatives modulate 5-LO, mPGES1, PPARα, and PPARγ at varying potencies [3][4][5][6][7][8] and these molecules are considered as potential anti-cancer drug targets [14][15][16][17]. However, the effects of the compounds on cancer cell viability did not correlate Table 8. with their effects on 5-LO, mPGES1, PPARα, or PPARγ activity (Suppl .…”

Section: Discussionmentioning

confidence: 99%

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

Michaelis¹,

Rothweiler²,

Wurglics³

et al. 2016

European Journal of Cancer

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Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARa, PPARg, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARa, and PPARg represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARa, or PPARg. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.

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Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity

Cited by 38 publications

References 48 publications

Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

Presenilin Is the Molecular Target of Acidic γ-Secretase Modulators in Living Cells

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

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