Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has a crucial role in cell death and inflammation. A promising approach to develop novel inhibitors of RIPK1 mediated necroptosis is to mix the different binding modes of the known RIPK1 inhibitors into one molecule. Herein we report the synthesis and biological evaluation of novel mixed type inhibitors.

Transaminase-catalysis to produce trans-4-substituted cyclohexane-1-amines including a key intermediate towards cariprazine.

Cariprazine-the only single antipsychotic drug in the market which can handle all symptoms of bipolar I disorder-involves trans-4-substituted cyclohexane-1-amine as a key structural element. In this work, production of trans-4-substituted cyclohexane-1-amines was investigated applying transaminases either in diastereotope selective amination starting from the corresponding ketone or in diastereomer selective deamination of their diasteromeric mixtures. Transaminases were identified enabling the conversion of the cis-diastereomer of four selected cis/trans-amines with different 4-substituents to the corresponding ketones.

Novel-Type GABA PAMs: Structure-Activity Relationship in Light of the Protein Structure.

Selecting a known HTS hit with the pyrazolo[1,5-]pyrimidine core, our project was started from CMPPE, and its optimization was driven by a ligand-based pharmacophore model developed on the basis of published GABA positive allosteric modulators (PAMs). Our primary goal was to improve the potency by finding new enthalpic interactions. Therefore, we included the lipophilic ligand efficiency (LLE or LipE) as an objective function in the optimization that led to a carboxylic acid derivative ().

Discovery of Novel Steroid-Based Histamine H Receptor Antagonists/Inverse Agonists.

Steroid-based histamine H receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent HR activity together with significant in vivo H antagonism.

Design, synthesis and biological evaluation of novel cyclic malonamide derivatives as selective RIPK1 inhibitors.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a key role in cell death and inflammation. RIPK1 is a well-established therapeutic target, due to the presence of a unique kinase-regulating allosteric pocket, which enables selective inhibition. Herein we used GSK2982772 as our starting point in our discovery campaign.

Optimization of Novel α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators and the Discovery of a Preclinical Development Candidate Molecule (RGH-560).

During optimization of a previously identified lead compound, attempts were made to optimize the reactive indole structural element, the suboptimal metabolic stability, as well as the low kinetic solubility. It was concluded that the indole was important for activity. With the aim of further improvements, more thorough modifications were also carried out.

6-Aryl-quinazolines as novel GABA receptor positive allosteric modulators.

The systemic use of GABA orthosteric agonist baclofen might be limited due to its detrimental properties: sedation and motor impairment. In contrast, GABA positive allosteric modulators produce less adverse effects. Using BHF-177 as a starting point, we found a new active scaffold: the 6-aryl-quinazoline scaffold.

hERG Optimization of Benzofuro-Pyridine and Pyrazino-Indole Derivatives as MCHR1 Antagonists.

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the antagonists of melanin concentrating hormone receptor 1 (MCHR1). The design, synthesis, and biological studies of novel MCHR1 antagonists based on benzofuro-pyridine and pyrazino-indole scaffold was performed.

HTS-based discovery and optimization of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor.

HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family.

C-N Bond Formation by Consecutive Continuous-Flow Reductions towards A Medicinally Relevant Piperazine Derivative.

A new, continuous-flow consecutive reduction method was developed for the C-N bond formation in the synthesis of the key intermediate of the antipsychotic drug cariprazine. The two-step procedure consists of a DIBAL-H mediated selective ester reduction conducted in a novel, miniature alternating diameter reactor, followed by reductive amination using catalytic hydrogenation on 5% Pt/C. The connection of the optimized modules was accomplished using an at-line extraction to prevent precipitation of the aluminum salt byproducts.

Discovery of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor: Scaffold hopping approach.

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized.

Discovery of novel steroidal histamine H receptor antagonists/inverse agonists. Part 2. Versatile steroidal carboxamide derivatives.

To further proceed with our previous work, novel steroid-based histamine H receptor antagonists were identified and characterized. Using an 'amine-to-amide' modification strategy at position 17, in vitro and in vivo potent monoamino steroid derivatives were found during the lead optimization. Usage of the non-basic amide moiety resulted in beneficial effects both in activity and selectivity.

Chemoenzymatic Dynamic Kinetic Resolution of Amines in Fully Continuous-Flow Mode.

In this study, lipase-mediated dynamic kinetic resolution (DKR) of various benzylic amines (1a-g) is presented which is realized in a so far unprecedented fully continuous-flow system. The DKR process applying sol-gel immobilized lipase B from Candida antarctica as biocatalyst, palladium on 3-aminopropyl-functionalized silica as racemization catalyst, isopropyl 2-ethoxyacetate as acylating agent, ammonium formate as hydrogen and nitrogen sources, and 2-methyl-2-butanol as solvent under regulated pressure provided the desired products in moderate to good yields with excellent enantiomeric excesses.

Discovery of novel steroidal histamine H receptor antagonists/inverse agonists.

Emerging from an HTS campaign, novel steroid-based histamine H receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H receptors were found.

Continuous Synthesis and Purification by Coupling a Multistep Flow Reaction with Centrifugal Partition Chromatography.

Continuous-flow multistep synthesis is combined with quasi-continuous final-product purification to produce pure products from crude reaction mixtures. In the nucleophilic aromatic substitution of 2,4-difluoronitrobenzene with morpholine followed by a heterogeneous catalytic hydrogenation, the desired monosubstituted product can be continuously separated from the co- and by-products in a purity of over 99 % by coupling a flow reactor sequence to a multiple dual-mode (MDM) centrifugal partition chromatography (CPC) device. This purification technique has many advantages over HPLC, such as higher resolution and no need for column replacement or silica recycling, and it does not suffer from irreversible adsorption.

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds.

Recent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps.

Recent patents on novel MCH1 receptor antagonists as potential anti-obesity drugs.

Today, the 'obesity pandemic' is one of the biggest health issues around the world. Melanin-concentrating hormone (MCH), a hypothalamic neuropeptide, is one of the most potent, central stimulators of feeding and it also attenuates energy expenditure. Inhibitions of the MCH receptor, the melanin-concentrating hormone receptor-1 (MCHR1), has attracted considerable attention as a potential anti-obesity drug, during the last decade.

Vascular action as the primary mechanism of cognitive effects of cholinergic, CNS-acting drugs, a rat phMRI BOLD study.

Concordant results of functional magnetic resonance imaging (fMRI) and behavioral tests prove that some non-blood-brain barrier-penetrating drugs produce robust central nervous system (CNS) effects. The anticholinergic scopolamine interferes with learning when tested in rats, which coincides with a negative blood-oxygen-level-dependent (BOLD) change in the prefrontal cortex (PFC) as demonstrated by fMRI. The peripherally acting butylscopolamine also evokes a learning deficit in a water-labyrinth test and provokes a negative BOLD signal in the PFC.

Bradykinin B1 receptor antagonists: a patent update 2009 - 2012.

Introduction: Due to the role of bradykinin B1 receptor (B1R) in pain and inflammation, B1R antagonists have been suggested as promising drug candidates in chronic pain states. The first disclosed B1R antagonists were peptidomimetics, however, during the last few years, novel chemotypes with improved pharmacodynamic and pharmacokinetic properties have been identified.

Areas Covered: In this review, we aim to give an overview on B1R antagonists published in patent applications between January 2009 and July 2012.

Quinolinyl- and phenantridinyl-acetamides as bradykinin B1 receptor antagonists.

A new series of quinolinyl- and phenantridinyl-acetamides were synthesizer and evaluated against bradykinin B1 receptor. In vitro metabolic stability data were reported for the key compounds.The analgesic effect of compound 20 from the phenantridine series was proved in-vivo.

Synthesis of vinca alkaloids and related compounds. 100. Stereoselective oxidation reactions of compounds with the aspidospermane and quebrachamine ring system. First synthesis of some alkaloids containing the epoxy ring.

The first syntheses of the alkaloids (-)-mehranine (3), (+)-voaphylline/conoflorine (4), (+)-N(a)-methylvoaphylline/hecubine (5), and (-)-lochnericine (2) were achieved by stereoselective epoxidation starting from (-)-tabersonine (1), through intermediates with the aspidospermane and quebrachamine skeleton.