Jens-Uwe Peters

Fenobam: A Clinically Validated Nonbenzodiazepine Anxiolytic Is a Potent, Selective, and Noncompetitive mGlu5 Receptor Antagonist with Inverse Agonist Activity

Fenobam [N-(3-chlorophenyl)-N′-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] is an atypical anxiolytic agent with unknown molecular target that has previously been demonstrated both in rodents and human to exert anxiolytic activity. Here, we report that fenobam is a selective and potent metabotropic glutamate (mGlu)5 receptor antagonist acting at an allosteric modulatory site shared with 2-methyl-6-phenylethynyl-pyridine (MPEP), the protypical selective mGlu5 receptor antagonist. Fenobam inhibited quisqualate-evoked intracellular calcium response mediated by human mGlu5 receptor with IC50 = 58 ± 2 nM. It acted in a noncompetitive manner, similar to MPEP and demonstrated inverse agonist properties, blocking 66% of the mGlu5 receptor basal activity (in an over expressed cell line) with an IC50 = 84 ± 13 nM. [3H]Fenobam bound to rat and human recombinant receptors with Kd values of 54 ± 6 and 31 ± 4 nM, respectively. MPEP inhibited [3H]fenobam binding to human mGlu5 receptors with a Ki value of 6.7 ± 0.7 nM, indicating a common binding site shared by both allosteric antagonists. Fenobam exhibits anxiolytic activity in the stress-induced hyperthermia model, Vogel conflict test, Geller-Seifter conflict test, and conditioned emotional response with a minimum effective dose of 10 to 30 mg/kg p.o. Furthermore, fenobam is devoid of GABAergic activity, confirming previous reports that fenobam acts by a mechanism distinct from benzodiazepines. The non-GABAergic activity of fenobam, coupled with its robust anxiolytic activity and reported efficacy in human in a double blind placebo-controlled trial, supports the potential of developing mGlu5 receptor antagonists with an improved therapeutic window over benzodiazepines as novel anxiolytic agents.

Pharmacological Promiscuity: Dependence on Compound Properties and Target Specificity in a Set of Recent Roche Compounds

What parameters determine promiscuity? A compounds potential for promiscuity (pharmacological activity at multiple targets) may be influenced by molecular parameters such as ionization state, lipophilicity, and molecular weight. In an analysis of recent Roche compounds we found that a positive charge is an important determinant for potential promiscuity; aminergic activity was found to be the main reason for overt promiscuity.

Tyramine fragment binding to BACE-1

Fragment screening revealed that tyramine binds to the active site of the Alzheimers disease drug target BACE-1. Hit expansion by selection of compounds from the Roche compound library identified tyramine derivatives with improved binding affinities as monitored by surface plasmon resonance. X-ray structures show that the amine of the tyramine fragment hydrogen-bonds to the catalytic water molecule. Structure-guided ligand design led to the synthesis of further low molecular weight compounds that are starting points for chemical leads.

11 Years of Cyanopyrrolidines as DPP-IV Inhibitors

Cyanopyrrolidines (cyanopyrrolidides, pyrrolidine-2-nitriles, prolinenitriles) as inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV, DP IV, CD26, EC 3.4.14.5) were first reported in 1995. The interest in this compound class grew immensely when DPP-IV was discovered as a target for the treatment of type 2 diabetes. The research on cyanopyrrolidines cumulated in the discoveries of vildagliptin (LAF237, NVP-LAF237) and saxagliptin (BMS-477118). These compounds entered Phase III clinical trials in 2004 and 2005, respectively, and an application for market approval has been filed for vildagliptin in 2006. Today cyanopyrrolidines are, as judged by the numbers of patent applications, the most prominent of several series of DPP-IV inhibitors, and have the potential to become valuable medicines for type 2 diabetes in the near future. This review summarizes some historical aspects of the discovery of cyanopyrrolidine DPP-IV inhibitors, and then focuses mainly on structure-activity-relationships, the evolution of different subseries, the possibilities to improve on the chemical instability that is associated with this compound class, and on the discoveries of vildagliptin and saxagliptin. Within this context, the properties of individual compounds and results from biological studies are discussed. The rationale of DPP-IV inhibition, clinical data, and the relevance of selectivity over related proteases are extensively reviewed in other contributions to this issue of Curr. Top. Med. Chem., and are therefore only very briefly touched.

Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators: Discovery of 2-Chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (Basimglurant, RO4917523), a Promising Novel Medicine for Psychiatric Diseases

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinsons disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.

Iminium ion catalysis: Use of the α-effect in the acceleration of the Diels–Alder reactionElectronic supplementary information (ESI) available: 1H NMR, 13C NMR, IR and MS spectra. See http://www.rsc.org/suppdata/cc/b2/b212239a/

The α-effect can be used in the acceleration of the Diels–Alder reaction between a series of dienes and electron deficient dienophiles using iminium ion catalysis, providing a novel molecular scaffold capable of performing this class of catalytic process.

Inhibitors of Dipeptidyl Peptidase IV - Recent Advances and Structural Views

Prevalence of type 2 diabetes has increased dramatically in the last decades. Current medicines are not yet capable to efficiently prevent or reverse progression of the disease and its associated comorbidities. As a consequence, there is a great need for novel antidiabetic drugs. Treatments of type 2 diabetes that are based on enhanced and sustained action of insulinotropic incretin hormones such as GLP-1 have received much attention in the past years. Treatment strategies include administration of: 1) GLP-1 analogues that are resistant to degradation by the serine protease DPP-IV, and 2) small molecule DPP-IV inhibitors that are able to provide sustained action of endogenous GLP-1, again by preventing its degradation. This review summarizes recent research results for the second approach. It briefly touches upon the advantages that treatment of type 2 diabetes with DPP-IV inhibitors may offer over current medications. In the main section, several important structural classes of DPP-IV inhibitors are described and compared based on literature data. Specific attention is given to the analysis of several X-ray structures of enzyme-inhibitor co-crystals. Finally, as clinical data are steadily emerging for some of the most advanced development candidates, the last section of this review is providing a brief overview of some efficacy data from recent clinical studies with DPP-IV inhibitors.

Metabolite Identification via LC-SPE-NMR-MS of the In vitro Biooxidation Products of a Lead mGlu5 Allosteric Antagonist and Impact on the Improvement of Metabolic Stability in the Series

Detailed information on the metabolic fate of lead compounds can be a powerful tool for an informed approach to the stabilization of metabolically labile compounds in the lead optimization phase. The combination of high performance liquid chromatography (HPLC) with nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) has been used to give comprehensive structural data on metabolites of novel drugs in development. Recently, increased automation and the embedding of on‐line solid‐phase extraction (SPE) into a integrated LC‐SPE‐NMR‐MS system have improved enormously the detection limits of this approach. The new technology platform allows the analysis of complex mixtures from microsome incubations, combining low material requirements with relatively high throughput. Such characteristics make it possible to thoroughly characterize metabolites of selected compounds at earlier phases along the path to lead identification and clinical candidate selection, thus providing outstanding guidance in the process of eliminating undesired metabolism and detecting active or potentially toxic metabolites. Such an approach was applied at the lead identification stage of a backup program on metabotropic glutamate receptor 5 (mGlu5) allosteric inhibition. The major metabolites of a lead 5‐aminothiazole‐4‐carboxylic acid amide 1 were synthesized and screened, revealing significant in vitro activity and possible involvement in the overall pharmacodynamic behavior of 1. The information collected on the metabolism of the highly active compound 1 was pivotal to the synthesis of related compounds with improved microsomal stability.

Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: optimization of in vitro activity.

Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providing lead compounds suitable for further optimization.

Discovery of potent, balanced and orally active dual NK1/NK3 receptor ligands.

During a program directed at selective NK(1) receptor antagonists, we serendipitously discovered an NK(1) receptor ligand with additional affinity for the NK(3) receptor. Recognising an opportunity for a drug discovery program aiming for dual NK(1)/NK(3) receptor antagonists, we prepared a series of analogues from a novel, versatile building block. From this series emerged compounds with high and balanced affinities for the NK(1) and the NK(3) receptors. Typical representatives of this series were active in the gerbil foot tapping assay after oral administration.