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

Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ 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, PPARα, or PPARγ.

Structural basis for the regulation of the mitogen-activated protein (MAP) kinase p38α by the dual specificity phosphatase 16 MAP kinase binding domain in solution.

Mitogen-activated protein kinases (MAPKs) fulfill essential biological functions and are key pharmaceutical targets. Regulation of MAPKs is achieved via a plethora of regulatory proteins including activating MAPKKs and an abundance of deactivating phosphatases. Although all regulatory proteins use an identical interaction site on MAPKs, the common docking and hydrophobic pocket, they use distinct kinase interaction motif (KIM or D-motif) sequences that are present in linear, peptide-like, or well folded protein domains.

Drugs by numbers: reaction-driven de novo design of potent and selective anticancer leads.

A potent and selective inhibitor of the anticancer target Polo-like kinase 1 was found by computer-based molecular design. This type II kinase inhibitor was synthesized as suggested by the design software DOGS and exhibited significant antiproliferative effects against HeLa cells without affecting nontransformed cells. The study provides a proof-of-concept for reaction-based de novo design as a leading tool for drug discovery.

Discovery of γ-secretase modulators with a novel activity profile by text-based virtual screening.

We present an integrated approach to identify and optimize a novel class of γ-secretase modulators (GSMs) with a unique pharmacological profile. Our strategy included (i) virtual screening through application of a recently developed protocol (PhAST), (ii) synthetic chemistry to discover structure-activity relationships, and (iii) detailed in vitro pharmacological characterization. GSMs are promising agents for treatment or prevention of Alzheimer's disease.

DOGS: reaction-driven de novo design of bioactive compounds.

We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated 'in silico' assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features.

SAR studies of acidic dual γ-secretase/PPARγ modulators.

A novel set of dual γ-secretase/PPARγ modulators characterized by a 2-benzyl hexanoic acid scaffold is presented. Synthetic efforts were focused on the variation of the substitution pattern of the central benzene. Finally, we obtained a new class of 2,5-disubstituted 2-benzylidene hexanoic acid derivatives, which act as dual γ-secretase/PPARγ modulators in the low micromolar range.

Identification of 2-mercaptohexanoic acids as dual inhibitors of 5-lipoxygenase and microsomal prostaglandin E₂ synthase-1.

5-Lipoxygenase (5-LO) and microsomal prostaglandin E₂ synthase (mPGES)-1 are key enzymes in the biosynthesis of leukotrienes and prostaglandin (PG)E₂, respectively, and are considered as valuable targets for the treatment of inflammatory diseases. Here, we present the identification of 2-mercaptohexanoic acid derivatives as dual inhibitors of 5-LO and mPGES-1. The lead compound 2(4-(3-biphenyloxypropoxy)phenylthio)hexanoic acid (21) inhibits human 5-LO and mPGES-1 in cell-free assays with an IC₅₀ = 3.

Reaction-driven de novo design, synthesis and testing of potential type II kinase inhibitors.

Background: De novo design of drug-like compounds with a desired pharmacological activity profile has become feasible through innovative computer algorithms. Fragment-based design and simulated chemical reactions allow for the rapid generation of candidate compounds as blueprints for organic synthesis.

Methods: We used a combination of complementary virtual-screening tools for the analysis of de novo designed compounds that were generated with the aim to inhibit inactive polo-like kinase 1 (Plk1), a target for the development of cancer therapeutics.

A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl pirinixic acid scaffold.

Dual inhibition of microsomal prostaglandin E(2) synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic acid cascade. Herein, a class of α-naphthyl pirinixic acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC(50) mPGES-1=0.

Functionalization of fatty acid mimetics for solid-phase coupling and subsequent target identification.

Fatty acid mimetics such as pirinixic acid (PA) derivatives and 2-(phenylthio)alkanoic acid derivatives are drug-like small molecules with an interesting pharmacological profile. Previously, we have characterized PA derivatives (e.g.

Exploring the chemical space of gamma-secretase modulators.

gamma-Secretase is a key enzyme in the pathophysiology of Alzheimer's disease (AD) and is responsible for the production of potentially toxic amyloid-beta (Abeta) 42 peptides. gamma-Secretase modulators (GSMs) are small molecules (<600 Da) causing a product shift from Abeta42 toward shorter and less toxic Abeta fragments. Classical non-steroidal anti-inflammatory drugs (NSAIDs) constituted the first class of GSMs, and therefore many of today's GSMs exhibit NSAID-like overall structure combining an acidic head group with a lipophilic backbone.

Design, synthesis, and biological evaluation of a novel class of gamma-secretase modulators with PPARgamma activity.

We present a novel class of dual modulators of gamma-secretase and peroxisome proliferator-activated receptor gamma (PPARgamma) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC(50)(Abeta42) = 22.8 microM, EC(50)(PPARgamma) = 8.3 microM).

Truxillic acid derivatives act as peroxisome proliferator-activated receptor gamma activators.

In previous studies, we identified a truxillic acid derivative as selective activator of the peroxisome proliferator-activated receptor gamma, which is a member of the nuclear receptor family and acts as ligand-activated transcription factor of genes involved in glucose metabolism. Herein we present the structure-activity relationships of 16 truxillic acid derivatives, investigated by a cell-based reporter gene assay guided by molecular docking analysis.

Nonacidic inhibitors of human microsomal prostaglandin synthase 1 (mPGES 1) identified by a multistep virtual screening protocol.

Microsomal prostaglandin E(2)-synthase (mPGES-1) is a target for future anti-inflammatory drugs. Inhibitors of mPGES-1 mimicking prostaglandin E(2) often interact with cyclooxygenases (COXs) 1 and 2, leading to unwanted side effects. Selective inhibitors of mPGES-1 can be obtained by deliberate abdication of the acidic groups, which are an important feature of COX inhibition.

The molecular pharmacology and in vivo activity of 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a dual inhibitor of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase.

The microsomal prostaglandin E(2) synthase (mPGES)-1 is one of the terminal isoenzymes of prostaglandin (PG) E(2) biosynthesis. Pharmacological inhibitors of mPGES-1 are proposed as an alternative to nonsteroidal anti-inflammatory drugs. We recently presented the design and synthesis of a series of pirinixic acid derivatives that dually inhibit mPGES-1 and 5-lipoxygenase.

Enantiomer separation and indirect chromatographic absolute configuration prediction of chiral pirinixic acid derivatives: Limitations of polysaccharide-type chiral stationary phases in comparison to chiral anion-exchangers.

Chiral alpha-arylthiocarboxylic acids with different substitution patterns, representing new pirinixic acid derivatives with dual PPARalpha/gamma agonistic activities, have been separated into enantiomers on tert-butylcarbamoylquinine and quinidine based chiral anion-exchangers and amylose tris(3,5-dimethylphenylcarbamate) coated silica on analytical and preparative scale. Absolute configurations of individual enantiomers were assigned chromatographically via elution orders on the chiral anion-exchangers and were confirmed by stereoselective syntheses via Ewans auxiliaries that have lead to enantiomeric products with known absolute configurations. The results of both methods were in full agreement.

Discovery of a novel class of 2-mercaptohexanoic acid derivatives as highly active PPARalpha agonists.

A novel and robust scaffold for highly active PPARalpha agonists based on the 2-mercaptohexanoic acid substructure is presented. Systematic structural variation of the substitution pattern of the phenolic backbone yielded detailed SAR especially of ortho and meta substituents. We corroborated the importance of the sulfur atom as well as of the n-butyl chain for PPARalpha activity in the 2-mercaptohexanoic acid head group by preparation of carbon analogs and alpha-unsubstituted derivatives.

Nonsteroidal anti-inflammatory drugs: a critical review on current concepts applied to reduce gastrointestinal toxicity.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs worldwide. Nevertheless, their intake is frequently associated with gastrointestinal side effects, representing still an important medical and socio-economic problem. In recent years efforts focused on the development of highly selective COX-2 inhibitors with an improved gastric tolerability profile.