Pyrazolo[4,3-c]isoquinolines as potential inhibitors of NF-kappaB activation.

In this work, we aimed to build a 3D-model of NIK and to study the binding of pyrazolo[4,3-c]isoquinolines with a view to highlight the structural elements responsible for their inhibitory potency. However, in the course of this work, we unexpectedly found that the pyrazolo[4,3-c]isoquinolines initially reported as NIK inhibitors were neither inhibitors of this enzyme nor of the alternative NF-kappaB pathway, but were in fact inhibitors of another kinase, the TGF-beta activated kinase 1 (TAK1) which is involved in the classical NF-kappaB pathway.

Discovery of a new class of non-imidazole oxazoline-based histamine H(3) receptor (H(3)R) inverse agonists.

H(3)R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.

4-benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists.

Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.

Alkyne-quinuclidine derivatives as potent and selective muscarinic antagonists for the treatment of COPD.

SAR around alkyne-quinuclidine derivatives allowed the discovery of highly potent muscarinic antagonists displaying interesting preferential slow off-rates from the M3 receptor.

SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy.

SV2A, a synaptic vesicle protein, has been recently identified as a binding target for levetiracetam (Keppra). The specific mechanism by which SV2A binding leads to seizure protection has not yet been fully elucidated. However, a functional correlation between SV2A binding affinity and anticonvulsant potency has been observed in the mouse audiogenic seizure model. The present study was undertaken to test whether similar correlations exist in rodent models of partial and generalized epilepsies. As expected, there was a high degree of correlation between anticonvulsant potency and SV2A binding affinity in the mouse audiogenic seizure model (r(2)=0.77; p<0.001). A similar correlation was also observed in the mouse corneal kindling (r(2)=0.80; p<0.01) and in the rat model of generalized absence epilepsy (GAERS) (r(2)=0.72; p<0.01). Moreover, there were no significant differences between the slopes and intercepts of regression lines in these models. Interestingly, the protective potencies in these three epilepsy models were also well correlated with each other. As such, protective doses of a given SV2A ligand in one model could be easily predicted based on the data obtained in another model. Taken together, these results support the concept that SV2A protein is an important target for both partial and generalized epilepsies and thereby relevant for the generation of new antiepileptic drugs with potential broad-spectrum efficacy.

Potent anti-muscarinic activity in a novel series of quinuclidine derivatives.

The synthesis and biological evaluation of a novel family of M(3) muscarinic antagonists are described. A systematic modification of the substituents to a novel alkyne-quinuclidine scaffold yielded original compounds displaying potent in vitro anticholinergic properties.

Keynote review: histamine H3 receptor antagonists reach out for the clinic.

Antagonists of the histamine H(1) and H(2) receptors have been successful as blockbuster drugs for treating allergic conditions and gastric ulcers, respectively. As such, histamine receptors have made a significant contribution to establishing G-Protein-coupled receptors as the favored drug targets of the industry. In this light, it can easily be understood that the discovery of a third histamine receptor subtype (H(3)R) in 1983 was greeted with considerable excitement. However, characterization of the H(3)R turned out to be far from trivial. In the past five years, molecular biology approaches have given fresh impetus to the H(3)R research field. As a result, H(3)R ligands are where they were anticipated to be 20 years ago: at the center of attention and on the verge of an anticipated breakthrough as the next generation of histaminergic blockbuster drugs. Here, we assess the status of the H(3)R medicinal chemistry programs of the various players in the field, as far as can be deduced from patent applications and scientific literature.

In vitro properties of 5-(benzylsulfonyl)-4-bromo-2-methyl-3(2H)-pyridazinone: a novel permeability transition pore inhibitor.

Despite the increasing implication of the permeability transition pore (PTP) in the pathophysiology of neurodegenerative diseases, few selective PTP inhibitors have been reported so far. Here, we evaluate the pharmacological properties of a novel PTP inhibitor, BBMP (5-(benzylsulfonyl)-4-bromo-2-methyl-3(2H)-pyridazinone). This drug was discovered from the screening of a compound library against the PTP using a functional assay with isolated mitochondria. Similarly to cyclosporin A, the drug prevented Ca2+-induced permeability transition and mitochondrial depolarization. BBMP appeared more potent that minocycline in both swelling and membrane potential assays displaying pIC50 values of 5.5+/-0.1 and 5.6+/-0.0, respectively. Unlike minocycline, BBMP dose-dependently prevented DNA fragmentation induced by KCl 25/5 mM shift and serum deprivation in cerebellar granule neurons with a pIC50 of 5.7+/-0.6. The inhibition of PTP-mediated cytochrome c release observed in isolated mitochondria at 10 and 100 microM may explain its neuroprotective properties in vitro. These data suggest that the mitochondrial PTP is potentially involved in neuronal cell death and that PTP inhibitors, like BBMP, may possess a therapeutic potential in neurodegenerative disorders.

Identification of 4-(1H-imidazol-4(5)-ylmethyl)pyridine (immethridine) as a novel, potent, and highly selective histamine H(3) receptor agonist.

In this study, the piperidine ring of immepip and its analogues was replaced by a rigid heterocyclic pyridine ring. Many compounds in the series exhibit high affinity and agonist activity at the human histamine H(3) receptor. Particularly, the 4-pyridinyl analogue of immepip (1c, immethridine) is identified as a novel potent and highly selective histamine H(3) receptor agonist (pK(i) = 9.07, pEC(50) = 9.74) with a 300-fold selectivity over the closely related H(4) receptor.

Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity.

(S)-alpha-ethyl-2-oxopyrrolidine acetamide 2 (levetiracetam, Keppra, UCB S.A.), a structural analogue of piracetam, has recently been approved as an add-on treatment of refractory partial onset seizures in adults. This drug appears to combine significant efficacy and high tolerability due to a unique mechanism of action. The latter relates to a brain-specific binding site for 2 (LBS for levetiracetam binding site) that probably plays a major role in its antiepileptic properties. Using this novel molecular target, we initiated a drug-discovery program searching for ligands with significant affinity to LBS with the aim to characterize their therapeutic potential in epilepsy and other central nervous system diseases. We systematically investigated the various positions of the pyrrolidone acetamide scaffold. We found that (i) the carboxamide moiety on 2 is essential for affinity; (ii) among 100 different side chains, the preferred substitution alpha to the carboxamide is an ethyl group with the (S)-configuration; (iii) the 2-oxopyrrolidine ring is preferred over piperidine analogues or acyclic compounds; (iv) substitution of positions 3 or 5 of the lactam ring decreases the LBS affinity; and (v) 4-substitution of the lactam ring by small hydrophobic groups improves the in vitro and in vivo potency. Six interesting candidates substituted in the 4-position have been shown to be more potent antiseizure agents in vivo than 2. Further pharmacological studies from our group led to the selection of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83alpha (ucb 34714) as the most interesting candidate. It is approximately 10 times more potent than 2 as an antiseizure agent in audiogenic seizure-prone mice. A clinical phase I program has been successfully concluded and 83alpha will commence several phase II trials during 2003.

Dual NK(1) antagonists--serotonin reuptake inhibitors as potential antidepressants. Part 2: SAR and activity of benzyloxyphenethyl piperazine derivatives.

The synthesis, structure-affinity relationship and activity of benzyloxyphenethyl piperazine derivatives combining NK(1) antagonism and serotonin reuptake inhibition is described. Compound 7u was shown to be active in animal models of 5-HT reuptake inhibition and central NK(1) receptor blockade, and was demonstrated to be orally active in an integrated model sensitive to both mechanisms. This class of compounds potentially represents a new generation of antidepressants.

First dual NK(1) antagonists-serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants.

Compounds combining NK(1) antagonism and serotonin reuptake inhibition are described, and potentially represent a new generation of antidepressants. Compound 24 displays good affinities for both the NK(1) receptor and the serotonin reuptake site (32 and 25 nM, respectively).

The plasma membrane: a target and hurdle for the development of anti-Abeta drugs?

The plasma membrane has been the subject of intense investigation in the search for anti-amyloidogenic drugs for the treatment of Alzheimer's disease. Studies have highlighted numerous toxic properties of the well-known amyloid Abeta peptide on neuronal membranes. In this respect recent experimental data suggest that an early step in amyloid toxicity might be intracellularly mediated. This suggests that effective anti-amyloidogenic agents must be able to readily cross the plasma membrane while at the same time, counteracting the deleterious effects of the Abeta peptide on the phospholipid bilayer. This review summarizes recent findings regarding amyloid-plasma membrane interactions and discusses their relevance for the design of novel, potential anti-Abeta drugs.