6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists.

A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED(50) of 5.5mg/kg in an animal model of anticonvulsant activity after oral dosage.

Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor.

Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes with a different selectivity profile. The key to achieve these objectives was to couple a structure-based design approach with intensive pharmacologic evaluation of selected compounds during the medicinal chemistry optimization process. Here, we report on the biologic characterization of the 2-morpholino pyrimidine derivative pan-PI3K inhibitor NVP-BKM120.

A macrocyclic HCV NS3/4A protease inhibitor interacts with protease and helicase residues in the complex with its full-length target.

Hepatitis C virus (HCV) infection is a global health burden with over 170 million people infected worldwide. In a significant portion of patients chronic hepatitis C infection leads to serious liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. The HCV NS3 protein is essential for viral polyprotein processing and RNA replication and hence viral replication.

A screen for enhancers of clearance identifies huntingtin as a heat shock protein 90 (Hsp90) client protein.

Mechanisms to reduce the cellular levels of mutant huntingtin (mHtt) provide promising strategies for treating Huntington disease (HD). To identify compounds enhancing the degradation of mHtt, we performed a high throughput screen using a hippocampal HN10 cell line expressing a 573-amino acid mHtt fragment. Several hit structures were identified as heat shock protein 90 (Hsp90) inhibitors.

Novel in vitro-in vivo extrapolation (IVIVE) method to predict hepatic organ clearance in rat.

Purpose: Drug elimination in the liver consists of uptake, metabolism, biliary excretion, and sinusoidal efflux from the hepatocytes to the blood. We aimed to establish an accurate prediction method for liver clearance in rats, considering these four elimination processes. In vitro assays were combined to achieve improved predictions.

Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.

A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compound 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.

LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice.

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), but the underlying pathophysiological mechanisms and the normal function of this large multidomain protein remain speculative. To address the role of this protein in vivo, we generated three different LRRK2 mutant mouse lines. Mice completely lacking the LRRK2 protein (knock-out, KO) showed an early-onset (age 6 weeks) marked increase in number and size of secondary lysosomes in kidney proximal tubule cells and lamellar bodies in lung type II cells.

Rule-Based Classification of Chemical Structures by Scaffold.

Databases for small organic chemical molecules usually contain millions of structures. The screening decks of pharmaceutical companies contain more than a million of structures. Nevertheless chemical substructure searching in these databases can be performed interactively in seconds.

Structure-activity relationship and pharmacokinetic studies of sotrastaurin (AEB071), a promising novel medicine for prevention of graft rejection and treatment of psoriasis.

Protein kinase C (PKC) isotypes have emerged as key targets for the blockade of early T-cell activation. Herein, we report on the structure-activity relationship and the detailed physicochemical and in vivo pharmacokinetic properties of sotrastaurin (AEB071, 1), a novel maleimide-based PKC inhibitor currently in phase II clinical trials. Most notably, the preferred uptake of sotrastaurin into lymphoid tissues is an important feature, which is likely to contribute to its in vivo efficacy.

Calcilytics: antagonists of the calcium-sensing receptor for the treatment of osteoporosis.

The only bone anabolic agents currently available on the market are based on the parathyroid hormone (PTH). Secretion of endogenous PTH is controlled by a calcium-sensing receptor at the surface of the parathyroid glands. Antagonists of this receptor (calcilytics) induce the release of the hormone.

Non-stoichiometric inhibition in biochemical high-throughput screening.

Introduction: Over the last 2 decades, high-throughput screening (HTS) has become one of the key strategies for the generation of new leads. Non-stoichiometric inhibition is one of the most extensively studied mechanisms responsible for the large percentage of hit compounds from biochemical screens that cannot be developed into leads. Therefore, HTS hit lists need to be sorted rapidly and efficiently into stoichiometrically binding inhibitors and compounds that affect enzyme activity non-stoichiometrically.

Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.

This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.

CYP3A time-dependent inhibition risk assessment validated with 400 reference drugs.

Although reversible CYP3A inhibition testing is well established for predicting the drug-drug interaction potential of clinical candidates, time-dependent inhibition (TDI) has become the focus of drug designers only recently. Failure of several late-stage clinical candidates has been attributed to TDI, and this mechanism is also suspected to play a role in liver toxicities often observed in preclinical species. Measurement of enzyme inactivation rates (k(inact) and K(I)) is technically challenging, and a great deal of variability can be found in the literature.

The quest for novel chemical matter and the contribution of computer-aided de novo design.

Identifying novel chemical matter is the focus of many drug discovery efforts. Through these efforts, computer-based de novo design of drug-like molecules, which aim to build an entire molecule 'from scratch', has emerged as a valuable approach to identify novel chemical matter. In this paper, the author discusses the recent research efforts that aim to build, in silico, more chemically accessible molecules, sample more efficiently the chemical space and rank the proposed molecules.

Genetic approaches to modeling anxiety in animals.

Anxiety disorders are a growing health problem world-wide. However, the causative factors, etiology, and underlying mechanisms of anxiety disorders, as for most psychiatric disorders, remain relatively poorly understood. The current status of clinical research indicates that anxiety traits and anxiety disorder in man have a genetic component, and therefore genetic modeling in animals is a logical approach to gain a greater insight into their neurobiology.

Alterations in the expression of neuronal chloride transporters may contribute to schizophrenia.

During brain development, neuronal stem cells and immature neurons express high and low levels of, respectively, the Cl(-) transporters NKCC1 and KCC2, which results in high intracellular Cl(-) concentrations. Under these circumstances chloride-flux through the GABA-A channel is from intracellular to extracellular and consequently GABA depolarizes rather than hyperpolarizes immature cells. This excitatory response is essential for neurodevelopment since it affects proliferation of the neuronal progenitor pool, neuronal differentiation, dendrite and synapse formation and integration into the existing neuronal network.

Conformational changes of calmodulin on calcium and Peptide binding monitored by film bulk acoustic resonators.

Film bulk acoustic resonators (FBAR) are mass sensitive, label-free biosensors that allow monitoring of the interaction between biomolecules. In this paper we use the FBAR to measure the binding of calcium and the CaMKII peptide to calmodulin. Because the mass of the calcium is too small to be detected, the conformational change caused by the binding process is measured by monitoring the resonant frequency and the motional resistance of the FBAR.

In vivo neutralization of naturally existing antibodies against linear alpha(1,3)-galactosidic carbohydrate epitopes by multivalent antigen presentation: a solution for the first hurdle of pig-to-human xenotransplantation.

Pig-to-human xenotransplantation of islet cells or of vascularized organs would offer a welcome treatment alternative for the ever-increasing number of patients with end-stage organ failure who are waiting for a suitable allograph. The main hurdle are preexisting antibodies, most of which are specific for 'Linear-B', carbohydrate epitopes terminated by the unbranched Gal-alpha(1,3)Gal disaccharide. These antibodies are responsible for the 'hyper-acute rejection' of the xenograft by complement mediated hemorrhage.

Affinity-based screening techniques: their impact and benefit to increase the number of high quality leads.

Importance Of The Field: The generation of new chemical leads as a starting point for drug development is a critical step in pharmaceutical drug discovery. High-throughput screening and the attached processes have rapidly evolved over the past few years to become one of the main sources for new leads by testing large compound libraries for activity against a target of interest in biochemical in vitro tests using the recombinant protein or cell-based assays. Very recently, the traditional functional assay read-out technologies are being complemented by biophysical methods which directly measure the physical interaction (affinity) between a low molecular weight compound and a target protein.

Influenza and meningococcal vaccinations are effective in healthy subjects treated with the interleukin-1 beta-blocking antibody canakinumab: results of an open-label, parallel group, randomized, single-center study.

The objective of this study was to evaluate the efficacy of influenza and meningococcal vaccines in healthy subjects exposed to the anti-interleukin-1β (anti-IL-1β) monoclonal antibody canakinumab. This was an open-label, parallel group, randomized, single-center study of healthy subjects (aged 18 to 45 years). At baseline, antibody (Ab) titers were measured and subjects were randomized (1:1) to a single 300-mg canakinumab dose administered subcutaneously (s.

Combined use of computational chemistry, NMR screening, and X-ray crystallography for identification and characterization of fluorophilic protein environments.

(19)F NMR screening of fluorinated fragments with different Local Environment of Fluorine, a.k.a.

Endocrine and behavioural responses to acute central CRF challenge are antagonized in the periphery and CNS, respectively, in C57BL/6 mice.

Corticotropin releasing factor (CRF) is a major mediator of central and peripheral responses to environmental stressors, and antagonism of its receptors (CRF-R1, -R2) is an active area of pharmacotherapeutic research for stress-related disorders. Stress responses include CRF activation of the hypothalamus-pituitary-adrenal axis and behavioural inhibition. Valid in vivo models for the study of these neuro-endocrine and -behavioural CRF pathways and their central-peripheral antagonism are important.

In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part I.

Pyrrolo[2,3-f]isoquinoline based amino acids, tetracyclic lactams and cyclic ketone analogues are described as novel MK2 inhibitors with IC(50) as low as 5nM and good selectivity profiles against a number of related kinases including ERK, p38alpha and JNKs. TNFalpha release was suppressed from human peripheral blood mononuclear cells (hPBMCs), and a representative compound inhibited LPS induced TNFalpha release in mice illustrating the potential of this series to provide orally active MK2 inhibitors.