Matthias Nettekoven

Biochemical and behavioural characterization of EMPA, a novel high‐affinity, selective antagonist for the OX2 receptor

Background and purpose:  The OX2 receptor is a G‐protein‐coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep‐wake state. Herein, we describe the in vitro and in vivo properties of a selective OX2 receptor antagonist, N‐ethyl‐2‐[(6‐methoxy‐pyridin‐3‐yl)‐(toluene‐2‐sulphonyl)‐amino]‐N‐pyridin‐3‐ylmethyl‐acetamide (EMPA).

Selective naphthalene H3 receptor inverse agonists with reduced potential to induce phospholipidosis and their quinoline analogs

We reported earlier the refinement of our initial five-point pharmacophore model for the Histamine 3 receptor (H(3)R), with a new acceptor feature important for binding and selectivity against the other histamine receptor subtypes 1, 2 and 4. This approach was validated with a new series of H(3)R inverse agonists: the naphthalene series. In this Letter, we describe our efforts to overcome the phospholipidosis flag identified with our initial lead compound (1a). During the optimization process, we monitored the potency of our molecules toward the H(3) receptor, their selectivity against H(1)R, H(2)R and H(4)R, as well as some key molecular properties that may influence phospholipidosis. Encouraged by the promising profile of the naphthalene series, we used our deeper understanding of the H(3)R pharmacophore model to lead us towards the quinoline series. This series is perceived to have intrinsic advantages with respect to its amphiphilic vector.

Discovery of benzoylpiperazines as a novel class of potent and selective GlyT1 inhibitors

Screening of the Roche compound library led to the identification of the benzoylpiperazine 7 as a structurally novel GlyT1 inhibitor. The SAR which was developed in this series resulted in the discovery of highly potent compounds displaying excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo efficacy after oral administration.

Accelerating drug discovery by integrative implementation of laboratory automation in the work flow.

Acceleration of the drug discovery process in pre-clinical pharmaceutical research is a highly desirable goal and combinatorial chemistry united with automation technology promised to accomplish this task. Through the accumulation of experience with automated devices over time it became evident that only by harmonisation and streamlining of work-flow procedures the efficiency of the overall process can be improved. An open architecture of efficient data management and appropriate utilisation of automated laboratory protocols provides the opportunity to react in a flexible and advisable way. Only an integrative workflow concept promotes the enhancement of the overall performance. However, the foundation of any efforts towards the accelerated synthesis of new and desired compound arrays lies in the development of reliable chemistry protocols amenable to solid- and solution phase chemistry.

A combinatorial approach towards 2-acyl-3-amino-indole derivatives

Abstract A widely applicable reaction sequence towards functionalised 2-acyl-3-amino-indole derivatives is presented. A set of 205 indole derivatives were prepared, in a solution phase combinatorial fashion, by coupling a reliable reaction protocol to a rapid purification system employing parallel filtration and application of automated reversed phase HPLC.

Novel Triazolopyrimidine-Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases

The cannabinoid receptor 2 (CB2) system is described to modulate various pathological conditions, including inflammation and fibrosis. A series of new heterocyclic small‐molecule CB2 receptor agonists were identified from a high‐throughput screen. Lead optimization gave access to novel, highly potent, and selective (over CB1) triazolopyrimidine derivatives. A preliminary structure–activity relationship was established, and physicochemical properties in this compound class were significantly improved toward better solubility, lipophilicity, and microsomal stability. An optimized triazolopyrimidine derivative, (3S)‐1‐[5‐tert‐butyl‐3‐[(1‐cyclopropyltetrazol‐5‐yl)methyl]triazolo[4,5‐d]pyrimidin‐7‐yl]pyrrolidin‐3‐ol (39), was tested in a kidney ischemia–reperfusion model, in which it showed efficacy at a dose of 10 mg kg−1 (p.o.). A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound 39 was also protective in a model of renal fibrosis. Oral treatment with 39 at 3 mg kg−1 per day significantly decreased the amount of fibrosis by ∼40 % which was induced by unilateral ureter obstruction.

Discovery of potent and selective histamine H3 receptor inverse agonists based on the 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one scaffold

A novel series of potent histamine H(3) receptor inverse agonists based on the 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one scaffold has been discovered. Several compounds display high selectivity over other histamine receptor subtypes and have favorable physicochemical properties, low potential for CYP450 enzyme inhibition and high metabolic stability in microsomal preparations. (R)-2-Cyclopropylmethyl-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (8t) showed good in vivo efficacy after per os application in an acute rat dipsogenia model of water intake.

Refinement of histamine H3 ligands pharmacophore model leads to a new class of potent and selective naphthalene inverse agonists.

The refinement of our original five point pharmacophore model for the H(3) receptor with the addition of a new acceptor feature is presented. The importance of this new acceptor feature for the binding and the selectivity against H(1), H(2) and H(4) has been validated using a newly synthesized naphthalene series. With the SAR deduced from several hundred naphthalene derivatives in various sub-classes the specific role of each pharmacophoric feature, by varying the geometry, size and charge of the molecules, was elucidated. This led to the discovery of a highly potent and selective new compounds series.

Aminothiazole Derivatives as Neuropeptide Y5 Receptor Ligands: Finding the Balance between Affinity and Physicochemical Properties

Neuropetide Y is a peptide of 36 amino acids that is widely distributed in the central and peripheral nervous systems. It mediates a number of physiological effects through its various receptor subtypes. Studies in animals have shown that neuropeptide Y is a powerful stimulus of food intake, and it has been demonstrated that the activation of neuropeptide Y5 (NPY5) receptors results in hyperphagia and decreased thermogenesis. Therefore, compounds that antagonize neuropeptide Y at the Y5 receptor subtype might represent an approach to the treatment of eating disorders such as obesity and hyperphagia. Although it has been suggested that the antagonism of the NPY5 receptor does have a major effect on feeding in rats, there is evidence to support the NPY receptor system in humans as a valuable target for the treatment of metabolic disorders. In the course of a medicinal chemistry program designed to identify novel NPY5 receptor antagonists, thiazole derivatives had been described as interesting scaffolds. Our research group previously reported specific substitution patterns on the thiazole scaffold that proved favorable for the compounds to bind the NPY5 receptor with IC50 values in the low nanomolar range, yet these molecules also had poor physicochemical properties. However, a favorable C=O···S interaction was identified that yielded promising, potent thiazole derivatives. As this scaffold offers ample opportunities for optimization, we turned our interest toward the influence of the nature and length of the linker that connects the thiazole to the sulfonamide moiety, and thus the potential of the resulting compounds to function as antagonists of the NPY5 receptor (Scheme 1). As mentioned above, low solubility was identified as a major disadvantage of these thiazole compounds. Therefore, an optimization cycle was added to improve the physicochemical property profile. This was monitored by measuring solubility and permeability by using the parallel artificial membrane permeation assay (PAMPA). A correlation analysis of pIC50 values and physicochemical properties was carried out to determine whether these two parameters could be optimized independently, or if the optimization of affinity would simultaneously yield an inferior (or superior) physicochemical profile. The results indicated that solubility and membrane permeability were positively correlated, whereas no direct correlation between pIC50 and solubility/membrane permeability was observed (Table 1). However, a principal components analysis

Combinatorial synthesis of libraries of indole derivatives.

The synthesis of two indole derivative libraries is described. 2-Acyl-3-amino-indoles 4 can easily be accessed by treatment of the intermediates 3 with bases in a one-pot reaction sequence whereas the reaction of the isolated intermediates 5 (R(3)=aromatic-, heteroaromatic, or cycloalkyl) with acid chlorides yielded the novel indole derivatives 6. The products were purified by reversed phase column chromatography and obtained in multi-milligram quantities in acceptable yields.