Discovery of 4H-pyrazolo[1,5-a]pyrimidin-7-ones as potent inhibitors of hepatitis C virus polymerase.

A series of 4H-pyrazolo[1,5-a]pyrimidin-7-one derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase. A number of these compounds exhibited potent activity in enzymatic assay. The synthesis and structure-activity relationship are also described.

Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs.

In the late 1980's reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H(1) binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H(1) assays.

A review of HCV protease inhibitors.

HCV NS3 serine protease mediates the cleavage of the HCV polyprotein to release the functional proteins that are essential for viral propagation. The inhibition of NS3 protease activity is expected to block HCV replication in infected host cells, and therefore protease inhibitors are a potential new treatment strategy for HCV. Several novel HCV protease inhibitors have been discovered, of which some have been clinically proven to be effective in achieving sustained virological response in patients with HCV genotype 1 at rates higher than those observed with the standard of care.

Tolerability and safety profile of posaconazole: evaluation of 18 controlled studies in healthy volunteers.

Background And Objectives: Antifungal agent utility can be limited by safety and tolerability concerns. Posaconazole is an extended-spectrum triazole antifungal agent for the treatment and prophylaxis of invasive fungal infection. The aim was to analyse the overall safety profile of posaconazole in healthy volunteers.

Design and discovery of 1,3-benzodiazepines as novel dopamine antagonists.

A series of novel 1,3-benzodiazapine based D1 antagonists was designed according to the understanding of pharmacophore models derived from SCH 23390 (1b), a potent and selective D1 antagonist. The new design features an achiral cyclic-amidine that maintains desired basicity. Solid phase synthesis was developed for SAR development of the novel dopamine antagonists.

C5a-stimulated recruitment of beta-arrestin2 to the nonsignaling 7-transmembrane decoy receptor C5L2.

C5L2 (or GPR77) is a high-affinity receptor for the complement fragment C5a and its desarginated product, C5a-desArg. Unlike the classical C5a receptor CD88, C5L2 does not couple to intracellular G-protein-signaling pathways but is thought to function as a decoy receptor. The authors show that stimulation of C5L2 with C5a and C5a-desArg induces redistribution of green fluorescent protein-labeled beta-arrestin2 to cytoplasmic vesicles.

The discovery of azepane sulfonamides as potent 11beta-HSD1 inhibitors.

Discovery of a series of azepine sulfonamides as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is described. SAR studies at the 4-position of the azepane ring have resulted in the discovery of a very potent compound 30 which has an 11beta-HSD1 IC(50) of 3.0nM.

Efficacy of desloratadine in intermittent allergic rhinitis: a GA(2)LEN study.

Background: The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines proposed a classification for allergic rhinitis based on the duration of symptoms (intermittent, persistent) rather than on the time of allergen exposure (seasonal, perennial). There is no placebo-controlled, randomized clinical trial on intermittent allergic rhinitis (IAR) to date. Desloratadine (DL) is recommended for the first-line treatment of seasonal and perennial allergic rhinitis.

Effects of oral posaconazole on the pharmacokinetics of atazanavir alone and with ritonavir or with efavirenz in healthy adult volunteers.

Background: Patients with HIV/AIDS are at increased risk for opportunistic fungal infections. These patients may require concomitant treatment with antiretrovirals and azole antifungals, and interactions between these classes of drugs should be anticipated.

Methods: A phase 1, open-label, randomized, crossover, drug interaction study was conducted to assess the pharmacokinetic effects of coadministration of posaconazole (400 mg twice daily), with atazanavir (ATV) (300 mg/d alone) and with ritonavir (100 mg/d) or with efavirenz (400 mg/d) in healthy volunteers.

Characterization of a murine keyhole limpet hemocyanin (KLH)-delayed-type hypersensitivity (DTH) model: role for p38 kinase.

Molecular and cellular assessment of dermal delayed-type hypersensitivity (DTH) responses is a useful approach for evaluating the mechanism of action (MOA) of immunomodulatory agents. In the present report, we characterized the delayed-type hypersensitivity response induced by keyhole limpet hemocyanin (KLH), and validated its utility by evaluating an immunomodulator, BIRB-796. Intradermal KLH challenge of the ear pinna following subcutaneous antigen sensitization resulted in a pronounced skin inflammation that peaked at 24-48h.

High-throughput evaluation of CYP1A1 and 2B1 induction in rat liver slices using a semi-automated system.

Drug candidates with the propensity to induce rat CYP1A1 or 2B1 isoforms are believed to possess a greater tendency to induce hepatic tumors in oncogenicity studies. We have previously published on a manual rat liver slice assay that showed a satisfactory relationship between in vitro CYP2B1 m-RNA induction using real time PCR and the ex vivo pentoxyresorufin O-dealkylase (PROD) activity in liver microsomes prepared from rats treated daily via the oral route for 14 consecutive days with inducers or non-inducers. We now describe this automated in vitro high throughput liver slice technique to screen out drug candidates that are potent rodent CYP1A1 and/or CYP2B1 inducers.

The role of exploratory drug metabolism and pharmacokinetics in new drug research: case study-selection of a thrombin receptor antagonist for development.

The rising costs and time associated with bringing new medicines to the market have created a need for a new paradigm for reducing the attrition rates of drug candidates in both preclinical and clinical development stages. Early appraisal of drug metabolism and pharmacokinetic (DMPK) parameters is now possible due to several higher throughput in vitro and in vivo screens. This knowledge of DMPK properties should not only shorten the timelines for the selection of drug candidates but also enhance the probability of their success for development.

The role of hyphenated chromatography-mass spectrometry techniques in exploratory drug metabolism and pharmacokinetics.

The advances in high-speed synthesis technologies have produced a large number of biologically active new chemical entities (NCEs) for developability assessment. Current drug discovery efforts have been focused on identifying drug metabolism and pharmacokinetic (DMPK) issues at the earliest possible stage in order to reduce the attrition rate of drug candidates during the development phase. Mass spectrometry (MS) has proven a powerful tool in providing rapid qualitative and quantitative measurements of drug molecules for DMPK studies in both drug discovery and development.

Potent aza-peptide derived inhibitors of HCV NS3 protease.

Chronic hepatitis C infection is the primary cause for cirrhosis of the liver and hepatocellular carcinoma leading to liver failure and transplantation. The etiological agent hepatitis C virus produces a single positive strand RNA that is processed further with the help of NS3 serine protease to produce mature virus. Inhibition of this protease can potentially be used to develop drugs for HCV infections.

Macrocyclic inhibitors of HCV NS3 protease.

Background: HCV NS3 is a serine protease that plays a pivotal role in catalyzing the cleavage of the single polyprotein encoded by HCV after infection of hepatocytes. Analysis of the X-ray crystal structure of the enzyme reveals a shallow catalytic site located on the surface of the protein, which has made development of inhibitors a formidable task. Attempts to discover leads by a traditional approach of screening of compound libraries have proved futile and, therefore, researchers have adopted a structure-based drug design.

GPR119 agonists: a promising new approach for the treatment of type 2 diabetes and related metabolic disorders.

Type 2 diabetes (T2D) and associated obesity have reached epidemic proportions, and there is an increasing need for orally effective agents that regulate glucose homeostasis with a concurrent reduction in body weight. GPR119, a class-A (rhodopsin-like) G protein-coupled receptor, expressed primarily in the human pancreas and gastrointestinal tract, has attracted considerable interest as a T2D drug target in the last three to five years. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion and increased levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide).

The importance of drug-target residence time.

The importance of kinetics in drug-target interactions, and particularly the residence time of a drug with its target, is increasingly recognized to play a pivotal role in determining both the efficacy and toxicity of a drug. Drug residence time can often be demonstrated to be a key differentiating factor between drugs that act upon a common target. Drug-target residence time can result in either favorable or unfavorable outcomes, and the use of such information could lead to the more efficient design of best-in-class drugs.

Personalized medicine: a paradigm for a sustainable pharmaceutical industry?

Personalized medicine is a custom-tailored approach to patient treatment based on individual genetic traits. In personalized medicine, a patient group is characterized by a clinical biomarker that has been correlated to a differential response to drug treatment. During the past decade, several developments in the understanding of the structure and function of the human genome have occurred that bring personalized medicine closer to becoming a reality.

Iron (III) citrate inhibits polyethylenimine-mediated transient transfection of Chinese hamster ovary cells in serum-free medium.

Recent advances in transient transfection protocols using polyethylenimine (PEI) as a transfection reagent have led to the development of economical methods that provide yields sufficient for industrial production of proteins for many preclinical needs. There are many variables that can be optimized to improve protein expression in transient transfection, and one of the most critical is the medium in which the cells are grown. While transfection with PEI works well in media containing serum, the biopharmaceutical industry is moving away from animal-derived components in media.

Constitutive activity of cannabinoid-2 (CB2) receptors plays an essential role in the protean agonism of (+)AM1241 and L768242.

Background And Purpose: Cannabinoid-2 (CB(2)) receptor-selective agonists have shown anti-nociceptive activity in models of neuropathic and inflammatory pain, and the two agonists most widely used, (+/-)AM1241 [(2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl-methanone] and L768242 [(2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone] (GW405833), have been suggested to be protean agonists. Here we investigated the role of the constitutive activity of CB(2) receptors in (+)AM1241 and L768242 protean agonism.

Experimental Approach: Pharmacological profiles of CB(2) receptor ligands were evaluated in Chinese hamster ovary cells expressing recombinant human (hCB(2)) or rat (rCB(2)) receptors, by measuring modulation of cAMP.

Continuous and intermittent dosing of lonafarnib potentiates the therapeutic efficacy of docetaxel on preclinical human prostate cancer models.

Lonafarnib is a potent, selective farnesyltransferase inhibitor (FTI) undergoing clinical studies for the treatment of solid tumors and hematological malignancies. Preclinically, a number of FTIs, including lonafarnib, interact with taxanes to inhibit cancer cell growth in an additive/synergistic manner. These observations provided rationale for investigating the effects of combining lonafarnib and docetaxel on preclinical prostate cancer models.

Diaminocyclobutenediones as potent and orally bioavailable CXCR2 receptor antagonists: SAR in the phenolic amide region.

A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various amide modifications and substitution on the left side phenyl ring were prepared and found to show significant inhibitory activities towards both CXCR2 and CXCR1 receptors.